Substituted piperazines, (1,4) diazepines, and 2,5-diazabicyclo (2.2.1) heptanes as histamine h1 and/or h3 antagonists or histamine h3 reverse antagonists

ABSTRACT

The present invention relates to novel piperazine and azepine derivatives having pharmacological activity, processes for their preparation, to compositions containing them and to their use in the treatment of neurodegenerative disorders including Alzheimer&#39;s disease.

The present application is a continuation application of U.S. Ser. No.10/531,758, filed 14 Apr. 2005, now allowed, which was a 35 U.S.C. §371United States National Phase Application of International ApplicationNo. PCT/EP2003/011423 filed 14 Oct. 2003, which claims priority fromGB0224084.4 filed 16 Oct. 2002.

The present invention relates to novel piperazine and azepinederivatives having pharmacological activity, processes for theirpreparation, to compositions containing them and to their use in thetreatment of neurodegenerative disorders including Alzheimer's disease.

WO 02/76925 (Eli Lilly) describes a series of compounds which areclaimed to be histamine H3 antagonists. WO 02/055496 (GlaxoSmithKline)describes a series of piperidine and piperazine derivatives which areclaimed to be inducers of LDL-receptor expression. WO 02/12214 (OrthoMcNeil Pharmaceutical Inc.) describes a series of substitutedaryloxyalkylamines which are claimed to be histamine H3 antagonists.

The histamine H3 receptor is expressed in both the mammalian centralnervous system (CNS), and in peripheral tissues (Leurs et al., (1998),Trends Pharmacol. Sci. 19, 177-183). Activation of H3 receptors byselective agonists or histamine results in the inhibition ofneurotransmitter release from a variety of different nerve populations,including histaminergic, adrenergic and cholinergic neurons (Schlickeret al., (1994), Fundam. Clin. Pharmacol. 8, 128-137). Additionally, invitro and in vivo studies have shown that H3 antagonists can facilitateneurotransmitter release in brain areas such as the cerebral cortex andhippocampus, relevant to cognition (Onodera et al., (1998), In: TheHistamine H3 receptor, ed Leurs and Timmerman, pp 255-267, ElsevierScience B.V.). Moreover, a number of reports in the literature havedemonstrated the cognitive enhancing properties of H3 antagonists (e.g.thioperamide, clobenpropit, ciproxifan and GT-2331) in rodent modelsincluding the five choice task, object recognition, elevated plus maze,acquisition of novel task and passive avoidance (Giovanni et al.,(1999), Behav. Brain Res. 104, 147-155). These data suggest that novelH3 antagonists and/or inverse agonists such as the current series couldbe useful for the treatment of cognitive impairments in neurologicaldiseases such as Alzheimer's disease and related neurodegenerativedisorders.

The present invention provides, in a first aspect, a compound of formula(I):

wherein:R¹ represents hydrogen, —C₁₋₆ alkyl, —C₁₋₆ alkoxy, —C₃₋₈ cycloalkyl,—C₁₋₆ alkyl-C₃₋₈ cycloalkyl, aryl, heterocyclyl, heteroaryl, —C₁₋₆alkyl-aryl, —C₁₋₆ alkyl-heteroaryl, —C₁₋₆ alkyl-heterocyclyl,-aryl-aryl, -aryl-heteroaryl, -aryl-heterocyclyl, -heteroaryl-aryl,-heteroaryl-heteroaryl, -heteroaryl-heterocyclyl, -heterocyclyl-aryl,-heterocyclyl-heteroaryl, -heterocyclyl-heterocyclyl,wherein R¹ may be optionally substituted by one or more substituentswhich may be the same or different, and which are selected from thegroup consisting of halogen, hydroxy, COOR¹⁵, cyano, —C₁₋₆ alkyl-cyano,nitro, oxo, trifluoromethyl, trifluoromethoxy, fluoromethoxy,difluoromethoxy, C₁₋₆ alkyl (optionally substituted by a COOR¹⁵ group),C₂₋₆ alkenyl (optionally substituted by a COOR¹⁵ group), C₂₋₆ alkynyl(optionally substituted by a COOR¹⁵ group), C₁₋₆ alkoxy (optionallysubstituted by a COOR¹⁵ group), pentafluoroethyl, C₁₋₆ alkoxy, C₂₋₆alkenoxy, aryl, arylC₁₋₆ alkyl, —CO-aryl (optionally substituted by ahalogen atom), —CO-heteroaryl, —C₁₋₆ alkyl-CO-aryl, arylC₁₋₆ alkoxy,C₁₋₆ alkylthio, C₁₋₆ alkoxyC₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₃₋₇cycloalkylC₁₋₆ alkoxy, C₁₋₆ alkoxycarbonyl, C₁₋₆ alkylsulfonyl, C₁₋₆alkylsulfinyl, C₁₋₆ alkylsulfonyloxy, C₁₋₆ alkylsulfonylC₁₋₆ alkyl,sulfonyl, arylsulfonyl, arylsulfonyloxy, arylsulfonylC₁₋₆ alkyl,aryloxy, C₁₋₆ alkylsulfonamido, C₁₋₆ alkylamido, C₁₋₆alkylsulfonamidoC₁₋₆ alkyl, C₁₋₆ alkylamidoC₁₋₆ alkyl, arylsulfonamido,arylcarboxamido, arylsulfonamidoC₁₋₆ alkyl, arylcarboxamidoC₁₋₆ alkyl,aroyl, aroylC₁₋₆ alkyl, arylC₁₋₆ alkanoyl, or a group —COR¹⁵, —NR¹⁵R¹⁶,—CONR¹⁵R¹⁶, —NR¹⁵COR¹⁶, —NR¹⁵SO₂R¹⁶, or —SO₂NR¹⁵R¹⁶,wherein R¹⁵ and R¹⁶ independently represent hydrogen, C₁₋₆ alkyl or C₃₋₈cycloalkyl or together may be fused to form a 5- to 7-memberednon-aromatic heterocyclic ring optionally interrupted by an O or S atomand optionally substituted by a halogen, C₁₋₆ alkyl or —C₁₋₆ alkylC₁₋₆alkoxy group;Z represents a bond, CO, N(R¹⁰)CO or SO₂, such that when R¹ representshydrogen, Z represents NR¹⁰CO;p is 1 or 2;m, n and r independently represent 0, 1 or 2;R² represents halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, cyano, amino ortrifluoromethyl, such that when n represents 2, two R² groups mayinstead be linked to form a phenyl ring;R⁴ represents C₁₋₆ alkyl, or when r represents 2, two R⁴ groups mayinstead together form a bridged CH₂, (CH₂)₂ or (CH₂)₃ group;R¹⁰ represents hydrogen or C₁₋₆ alkyl, or R¹⁰, together with thenitrogen to which it is attached and R¹ forms a nitrogen containingheterocyclic group;R³ represents —(CH₂)_(q)—NR¹¹R¹² or a group of formula (I):

wherein q is 2, 3 or 4;R¹¹ and R¹² independently represent C₁₋₆ alkyl or C₃₋₈ cycloalkyl ortogether with the nitrogen atom to which they are attached represent anN-linked nitrogen containing heterocyclyl group optionally substitutedby one or more R¹⁷ groups;R¹³ represents hydrogen, C₁₋₆ alkyl, —C₁₋₆ alkyl-C₁₋₆ alkoxy, C₃₋₈cycloalkyl, —C₁₋₆ alkyl-C₃₋₈ cycloalkyl, —C₁₋₆ alkyl-aryl orheterocyclyl;R¹⁴ and R¹⁷ independently represent halogen, C₁₋₆ alkyl, haloalkyl, OH,diC₁₋₆ alkylamino, C₁₋₆ alkoxy or heterocyclyl;f and k independently represent 0, 1 or 2;g is 0, 1 or 2 and h is 0, 1, 2 or 3, such that g and h cannot both be0; with the proviso that when m represents 1, n and r both represent 0and R³ represents —(CH₂)₃—N-piperidine or —(CH₂)₃—N(ethyl)₂, R¹-Zrepresents a group other than methyl, —CO—O—C(CH₃)₃ or benzyl;and with the proviso that when m, n and r all represent 0, p represents1, R³ represents —(CH₂)₃—N-pyrrolidine or —(CH₂)₃—N-piperidine, R¹represents benzyl, Z represents a group other than a bond;and with the proviso that when m, n and r all represent 0, p represents1, R³ represents —(CH₂)₃—N-piperidine, R¹ represents isopropyl, Zrepresents a group other than a bond;and with the proviso that when m represents 1, n and r both represent 0,p represents 1, R³ represents —(CH₂)₃—N-piperidine, R¹ representsmethyl, isopropyl, aryl or benzyl, Z represents a group other than abond;and with the proviso that when m and n both represent 0, R³ represents—(CH₂)₃—N(ethyl)₂, p represents 1, r represents 2 and R¹ and R⁴ bothrepresent methyl, Z represents a group other than a bond;or a pharmaceutically acceptable salt thereof.

In one particular aspect of the present invention, there is provided acompound of formula (I) as defined above wherein:

R¹ represents a group other than hydrogen, —C₁₋₆ alkoxy or —C₁₋₆alkyl-C₃₋₈ cycloalkyl; andR¹ is optionally substituted by one or more substituents other thanCOOR¹⁵, —C₁₋₆ alkyl-cyano, C₁₋₆ alkyl substituted by a COOR¹⁵ group),C₂₋₆ alkenyl (optionally substituted by a COOR¹⁵ group), C₂₋₆ alkynyl(optionally substituted by a COOR¹⁵ group), C₁₋₆ alkoxy (optionallysubstituted by a COOR¹⁵ group), C₂₋₆ alkenoxy, aryl, arylC₁₋₆ alkyl,—CO-aryl (optionally substituted by a halogen atom), —CO-heteroaryl,—C₁₋₆ alkyl-CO-aryl or C₃₋₇ cycloalkyl; andR¹⁵ and R¹⁶ independently represent a group other than C₃₋₈ cycloalkylor together may be fused to form an unsubstituted 5- to 7-memberednon-aromatic heterocyclic ring optionally interrupted by an O or S atom;andr represents 0; andtwo R² groups are not linked to form a phenyl ring; andR¹¹ and R¹² independently represent a group other than C₃₋₈ cycloalkyl;andR¹³ represents a group other than —C₁₋₆ alkyl-C₃₋₈ cycloalkyl.

In a second particular aspect of the present invention, there isprovided a compound of formula (I) as defined above wherein m represents0 or 2.

In a further particular aspect of the present invention, there isprovided a compound of formula (I) as defined above wherein Z representsCO, CONR¹⁰ or SO₂.

Alkyl groups, whether alone or as part of another group, may be straightchain or branched and the groups alkoxy and alkanoyl shall beinterpreted similarly. Alkyl moieties are more preferably C₁₋₄ alkyl,eg. methyl or ethyl. The term ‘halogen’ is used herein to describe,unless otherwise stated, a group selected from fluorine, chlorine,bromine or iodine.

The term “aryl” includes single and fused rings wherein at least onering is aromatic, for example, phenyl, naphthyl, tetrahydronaphthalenyl,indanyl or fluorenyl.

The term “heterocyclyl” is intended to mean a 4-7 membered monocyclicsaturated or partially unsaturated ring or a 4-7 membered saturated orpartially unsaturated ring fused to a benzene ring containing 1 to 3heteroatoms selected from oxygen, nitrogen or sulphur. Suitable examplesof such monocyclic rings include pyrrolidinyl, piperidinyl, piperazinyl,morpholinyl, thiomorpholinyl, tetrahydrofuranyl, diazepanyl, azepanyland azocanyl. Suitable examples of benzofused heterocyclic rings includeindolinyl, isoindolinyl, benzodioxolyl and dihydroisoquinolinyl.

The term “nitrogen containing heterocyclyl” is intended to represent anyheterocyclyl group as defined above which contains a nitrogen atom.

The term “heteroaryl” is intended to mean a 5-7 membered monocyclicaromatic or a fused 8-11 membered bicyclic aromatic ring containing 1 to3 heteroatoms selected from oxygen, nitrogen and sulphur. Suitableexamples of such monocyclic aromatic rings include thienyl, furyl,pyrrolyl, triazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl,isothiazolyl, isoxazolyl, thiadiazolyl, pyrazolyl, pyrimidyl,pyridazinyl, pyrazinyl and pyridyl. Suitable examples of such fusedaromatic rings include furopyridinyl and benzofused aromatic rings suchas quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, cinnolinyl,naphthyridinyl, indolyl, indazolyl, pyrrolopyridinyl, benzofuranyl,benzothienyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl,benzothiazolyl, benzisothiazolyl, benzoxadiazolyl, benzothiadiazolyl andthe like.

Compounds of formula (I) and their pharmaceutically acceptable saltshave affinity for and are antagonists and/or inverse agonists of thehistamine H3 receptor and are believed to be of potential use in thetreatment of neurological diseases including Alzheimer's disease,dementia, age-related memory dysfunction, mild cognitive impairment,cognitive dysfunction, epilepsy, neuropathic pain, inflammatory pain,migraine, Parkinson's disease, multiple sclerosis, stroke and sleepdisorders including narcolepsy; psychiatric disorders includingschizophrenia, attention deficit hypereactivity disorder, depression andaddiction; and other diseases including obesity, asthma, allergicrhinitis, nasal congestion, chronic obstructive pulmonary disease andgastro-intestinal disorders.

Thus the invention also provides a compound of formula (I) or apharmaceutically acceptable salt thereof, for use as a therapeuticsubstance in the treatment or prophylaxis of the above disorders, inparticular cognitive impairments in diseases such as Alzheimer's diseaseand related neurodegenerative disorders.

Preferably, R¹ represents:

-   -   hydrogen;    -   C₁₋₆ alkyl (eg. methyl, methylbutyl, or propyl);    -   C₁₋₆ alkoxy (eg. —OC(CH₃)₃);    -   aryl (eg. phenyl, naphthyl, tetrahydronaphthyl, indanyl or        fluorenyl);    -   heteroaryl (eg. benzofuranyl, indolyl, pyrazinyl,        benzoxadiazolyl, thiadiazolyl, thienyl, pyrazolopyrimidinyl,        pyrazolopyridinyl, benzothiazolyl, furopyridinyl, pyridyl,        quinolinyl, isoquinolinyl, quinoxalinyl, cinnolinyl, thiazolyl,        triazolyl, isoxazolyl, pyrimidinyl, naphthyridinyl,        benzisoxazolyl or benzisothiazolyl);    -   heterocyclyl (eg. benzodioxolyl, pyrrolidinyl, piperidinyl,        piperazinyl, morpholinyl, thiomorpholinyl,        tetrahydrothiopyranyl, thiopyranyl, tetrahydropyranyl,        dihydrobenzofuranyl, dihydrochromenyl and xanthenyl);    -   C₃₋₈ cycloalkyl (eg. cyclopropyl, cyclopentyl or cyclohexyl);    -   —C₁₋₆ alkyl-aryl (eg. benzyl);    -   —C₁₋₆ alkyl-C₃₋₈ cycloalkyl (eg. —CH₂-cyclopropyl);    -   —C₁₋₆ alkyl-heteroaryl (eg. —CH₂-pyridyl, —CH₂-tetrazolyl,        —CH₂-triazolyl, —CH₂-isothiazolyl, —CH₂-thienyl or        —CH₂-furanyl);    -   -aryl-heterocyclyl (eg. phenyl-pyrrolidinyl);    -   -aryl-aryl (eg. -biphenyl);    -   -aryl-heteroaryl (eg. -phenyl-pyridyl, -phenyl-pyrrolyl or        -phenyl-tetrazolyl); or    -   -heteroaryl-aryl (eg. pyridyl-phenyl).

More preferably, R¹ represents unsubstituted phenyl.

Also more preferably, R¹ represents:

-   -   aryl (eg. phenyl); or    -   heterocyclyl (eg. piperidinyl, piperazinyl, morpholinyl,        thiomorpholinyl or tetrahydropyranyl).

Preferably, R¹ is optionally substituted by one or more (eg. 1, 2 or 3):halogen (eg. chlorine, fluorine or bromine); trifluoromethyl; —C₁₋₆alkyl (eg. methyl, ethyl, isopropyl, propyl or t-butyl) optionallysubstituted by COOR¹⁵ (eg. COOH, COOMe or COOEt); —C₁₋₆ alkoxy (eg.methoxy, butoxy, —OCH(Me)₂ or —OC(Me)₃) optionally substituted by COOR¹⁵(eg. COOH or COOMe); hydroxy; oxo; cyano; —C₁₋₆ alkyl-cyano (eg.—CH₂—CN); C₁₋₆ alkenyl (eg. ethenyl) optionally substituted by COOR¹⁵(eg. COOMe); C₃₋₇ cycloalkyl (eg. cyclopentyl); C₁₋₆ alkylsulfonyl (eg.SO₂Me); C₁₋₆ alkenoxy (eg. —OCH₂CH═CH₂); C₁₋₆ alkylthio (eg. —S-ethyl);NR¹⁵R¹⁶ (eg. N(Me)₂); —C₁₋₆ alkyl-aryl (eg. benzyl); aryl (eg. phenyl);—CO-aryl (eg. —CO-phenyl) optionally substituted by halogen (eg.chlorine); —CO-heteroaryl (eg. —CO-azetidinyl); —CO-heterocyclyl (eg.—CO-tetrahydropyranyl); —COOR¹⁵ (eg. COOH, COOMe or COOt-butyl); —COR¹⁵(eg. —CO-methyl, —CO-ethyl, —CO-isopropyl, —CO-cyclopropyl,—CO-cyclobutyl, —CO-cyclopentyl or —CO-cyclohexyl); —CONR¹⁵R¹⁶ (eg.—CONH₂, —CO-pyrrolidinyl, —CO-morpholinyl, —CO-piperazinyl,—CO-piperidinyl, —CO-thiomorpholinyl) optionally substituted by C₁₋₆alkyl (eg. methyl), halogen (eg. fluorine) or —C₁₋₆ alkylC₁₋₆ alkoxy(eg. —CH₂—OMe); or —C₁₋₆ alkyl-CO-aryl (eg. —CH₂COphenyl) groups.

More preferably, R¹ is optionally substituted by one or more (eg. 1, 2or 3): halogen (eg. fluorine); oxo; cyano; —CONR¹⁵R¹⁶ (eg.—CO-pyrrolidinyl) or —COR¹⁵ (eg. —CO-isopropyl, —CO-cyclopropyl or—CO-cyclobutyl).

Preferably, Z represents a bond, CO or CONR¹⁰. More preferably, Zrepresents bond or CO, especially CO.

Preferably, R¹⁰ represents hydrogen or C₁₋₆ alkyl.

Preferably, m is 0 or 2, more preferably 0.

Preferably, n is 0 or 1, more preferably n is 0.

When n represents 1, R² is preferably halogen (eg. chlorine, bromine orfluorine), trifluoromethyl, cyano or C₁₋₆ alkyl (eg. methyl).

Preferably, r is 0.

When r represents 1 or 2, R² is preferably C₁₋₆ alkyl (eg. methyl) ortwo R⁴ groups together form a bridged CH₂ group.

Preferably, p is 1.

Preferably, R³ represents —(CH₂)_(q)—NR¹¹R¹².

When R³ represents a group of formula (I), preferably f is 0 or 1, g is2, h is 1, k is 0 and R¹³ represents hydrogen, optionally substitutedC₁₋₆ alkyl (eg. ethyl, methylpropyl, isopropyl or methoxyethyl), C₃₋₈cycloalkyl (eg. cyclopropyl, cyclobutyl or cyclopentyl) or —C₁₋₆alkyl-C₃₋₈ cycloalkyl (eg. —CH₂-cyclopropyl).

When R³ represents a group of formula (I), more preferably f is 0, g is2, h is 1, k is 0 and R¹³ represents C₁₋₆ alkyl (eg. isopropyl) or C₃₋₈cycloalkyl (eg. cyclopropyl or cyclobutyl).

Preferably, q is 2 or 3, more preferably 3.

Preferably, R¹¹ and R¹² independently represent C₁₋₆ alkyl (eg. methyl)or C₃₋₈ cycloalkyl (eg. cyclopentyl) or NR¹¹R¹² represents aheterocyclic group (eg. piperidinyl, pyrrolidinyl, thiomorpholinyl,azepanyl or azocanyl optionally substituted by one or more halogen (eg.fluorine) or C₁₋₆ alkyl (eg. methyl or ethyl).

More preferably NR¹¹R¹² represents pyrrolidinyl, piperidinyl, azepanylor azocanyl optionally substituted by one or more C₁₋₆ alkyl (eg. methylor ethyl), especially unsubstituted piperidine.

Preferably, —O—R³ is present at the para position of the phenyl groupwith respect to the rest of the compound.

Preferred compounds according to the invention include examples E1-E503as shown below, or a pharmaceutically acceptable salt thereof.

Compounds of formula (I) may form acid addition salts with acids, suchas conventional pharmaceutically acceptable acids, for example maleic,hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic,sulphuric, citric, lactic, mandelic, tartaric and methanesulphonic.Salts, solvates and hydrates of compounds of formula (I) therefore forman aspect of the invention.

Certain compounds of formula (I) are capable of existing instereoisomeric forms. It will be understood that the inventionencompasses all geometric and optical isomers of these compounds and themixtures thereof including racemates. Tautomers also form an aspect ofthe invention. For example, when R³ represents (CH₂)_(q)NR¹¹R¹² andNR¹¹R¹² represents a nitrogen containing heterocyclyl group substitutedby one or more C₁₋₆ alkyl groups it will be appreciated that the presentinvention extends to cover diastereomeric and enantiomeric compounds.

The present invention also provides a process for the preparation of acompound of formula (I) or a pharmaceutically acceptable salt thereof,which process comprises:

(a) reacting a compound of formula (II)

wherein R¹, Z, R⁴, p, m, r, R² and n are as defined above, with acompound of formula R^(3′)-L¹, wherein R^(3′) is as defined above for R³or a group convertible thereto and L¹ represents a suitable leavinggroup such as a halogen atom (eg. bromine or chlorine) or an optionallyactivated hydroxyl group; or(b) preparing a compound of formula (I) wherein Z represents CO byreacting a compound of formula (III)

or a protected derivative thereof, wherein R⁴, r, p, m, R², n and R³ areas defined above, with a compound of formula R¹—COX, wherein R¹ is asdefined above and X represents a suitable leaving group such as anactivated hydroxy group, a suitable halogen atom or benzotriazolyl; or(c) preparing a compound of formula (I) wherein Z represents SO₂ byreacting a compound of formula (III) as defined above with a compound offormula R¹—SO₂Cl, wherein R¹ is as defined above; or(d) preparing a compound of formula (I) wherein Z represents NR¹⁰CO byreacting a compound of formula (III) as defined above with a compound offormula R¹—N═C═O, wherein R¹ is as defined above; or(e) preparing a compound of formula (I) wherein Z represents CONR¹⁰ byreacting a compound of formula (III) as defined above, sequentially withphosgene in a solvent such as toluene followed by a compound of formulaR¹⁰R¹—NH, in a solvent such as dichloromethane, wherein R¹ and R¹⁰ areas defined above; or(f) preparing a compound of formula (I) wherein m represents 1 byreacting a compound of formula (IV)

with a compound of formula (XI)

or an optionally protected derivative thereof, wherein R⁴, r, R², n, R³,R¹, Z and p are as defined above under reducing conditions; or(g) deprotecting a compound of formula (I) which is protected; and(h) interconversion to other compounds of formula (I).

When R³ represents —(CH₂)_(q)—NR¹¹R¹², process (a) typically comprisesthe use of a suitable base, such as potassium carbonate in anappropriate solvent such as 2-butanone optionally in the presence of anactivating reagent such as potassium iodide at an appropriatetemperature such as reflux.

When a group R^(3′) convertible to R³ represents, for example,L²-(CH₂)_(q)—, process (a) typically comprises an alkylation reactionusing analogous conditions to those described above.

When R³ represents a group of formula (I) and L¹ represents anoptionally activated hydroxyl group, process (a) typically comprises theuse of a phosphine such as triphenylphosphine in a suitable solvent suchas tetrahydrofuran, followed by addition of an azodicarboxylate such asdiethylazodicarboxylate at a suitable temperature such as roomtemperature.

Process (b) typically comprises the use of an appropriate solvent suchas dichloromethane optionally in the presence of an organic or inorganicbase such as potassium carbonate or in the presence of a suitablecoupling agent such as 1,3-dicyclohexylcarbodiimide and1-hydroxybenzotriazole.

Processes (c) and (d) typically comprise the use of a suitable solventsuch as 2-butanone.

Process (e) typically comprises the use of a suitable base, such astriethylamine.

Process (f) comprises the use of reductive conditions (such as treatmentwith a borohydride eg. sodium triacetoxyborohydride), optionally in thepresence of an acid, such as acetic acid, followed by optionaldeprotection in the event that the compound of formula (XI) is aprotected derivative.

In process (g), examples of protecting groups and the means for theirremoval can be found in T. W. Greene ‘Protective Groups in OrganicSynthesis’ (J. Wiley and Sons, 1991). Suitable amine protecting groupsinclude sulphonyl (e.g. tosyl), acyl (e.g. acetyl,2′,2′,2′-trichloroethoxycarbonyl, benzyloxycarbonyl or t-butoxycarbonyl)and arylalkyl (e.g. benzyl), which may be removed by hydrolysis (e.g.using an acid such as hydrochloric acid in dioxan or trifluoroaceticacid in dichloromethane) or reductively (e.g. hydrogenolysis of a benzylgroup or reductive removal of a 2′,2′,2′-trichloroethoxycarbonyl groupusing zinc in acetic acid) as appropriate. Other suitable amineprotecting groups include trifluoroacetyl (—COCF₃) which may be removedby base catalysed hydrolysis or a solid phase resin bound benzyl group,such as a Merrifield resin bound 2,6-dimethoxybenzyl group (Ellmanlinker), which may be removed by acid catalysed hydrolysis, for examplewith trifluoroacetic acid.

Process (h) may be performed using conventional interconversionprocedures such as epimerisation, oxidation, reduction, alkylation,nucleophilic or electrophilic aromatic substitution, ester hydrolysis oramide bond formation. For example, compounds of formula (I) wherein R³represents a group of formula (I) may be interconverted at the R¹³position by reaction with an alkyl halide such as1-chloro-2-methoxyethane in the presence of a base such as potassiumcarbonate in a suitable solvent such as 2-butanone optionally in thepresence of a transfer reagent such as potassium iodide. Suchinterconversion may also be carried out by reductive amination, forexample, with acetone in the presence of a borohydride such as sodiumtriacetoxyborohydride and optionally an acid such as acetic acid in asuitable solvent such as dichloromethane.

Compounds of formula (II) and (III) wherein m is 1 or 2 may be preparedin accordance with the following scheme:

wherein R⁴, r, R², n, R³, p are as defined above and the compound offormula (V) may be optionally protected.

Step (i) may be performed in an analogous manner to that described forprocess (f) above.

Compounds of formula (III) wherein m is 0 may be prepared in accordancewith the following scheme:

wherein R⁴, r, p, R², n and R³ are as defined above and P¹ represents asuitable protecting group (such as Boc).

Step (i) may be performed when P¹ represents Boc by reacting a compoundof formula (IX) with di-t-butyl carbonate in the presence of a suitablebase (eg. triethylamine) in the presence of a suitable solvent (eg.dichloromethane) at a suitable temperature (eg. room temperature).

Step (ii) may be performed in an analogous manner to the proceduresshown below for the preparation of compounds of formula (IV).

Step (iii) typically comprises a deprotection reaction, for example,when P¹ represents Boc, deprotection may typically comprise reaction ofa compound of formula (III) P' with hydrochloric acid in dioxan ortrifluoroacetic acid in dichloromethane.

Compounds of formula (III) wherein m is 2 may be prepared in accordancewith the following scheme:

wherein R², R³, R⁴, n, p, r are as defined above, P² represents asuitable protecting group such as Boc and L⁵ represents a suitableleaving group such as a halogen atom (eg. bromine).

Step (i) typically comprises reaction of a compound of formula (XII)with a compound of formula (XIII) in the presence of an inert solventsuch as dimethylformamide or acetonitrile.

Step (ii) typically comprises a deprotection reaction, for example, whenP² represents Boc, deprotection may typically comprise reaction of acompound of formula (III)^(pii) with hydrochloric acid in dioxan ortrifluoroacetic acid in dichloromethane.

Compounds of formula (IV) wherein R³ represents —(CH₂)_(q)—NR¹¹R¹² maybe prepared in accordance with the following scheme:

wherein R², n, q, R¹¹, R¹² are as defined above and L¹, L², L³ and L⁴represent suitable leaving groups (eg. halogen atoms, such as bromine orchlorine).

Steps (i), (ii) and (iii) may be performed using similar conditions tothose described for process (a) above.

Compounds of formula (IV) wherein R³ represents a group of formula (I)as defined above may be prepared in accordance with the followingscheme:

wherein R², n, f, g, h, k, are as defined above, L⁴ represents asuitable leaving group such as a halogen atom or a hydroxyl group andR^(13a) is as defined above for R¹³ or a protecting group such ast-butoxycarbonyl, followed by optional deprotection.

Step (i) may be performed using similar conditions to those describedfor process (a) above.

Compounds of formula (II) wherein m is 0 may be prepared by adeprotection reaction of a compound of formula (IX) as defined above,followed by an analogous process to those described in processes (b),(c), (d) and (e) above, optionally followed by hydrolysis treatment tore-generate the free hydroxyl group of formula (II).

Compounds of formula (II) wherein m is 1 or 2 may be prepared from acompound of formula (IV) as defined above in an analogous process tothat defined above to prepare compounds of formula (III)^(a) followed byan analogous process to those described in processes (b), (c), (d) and(e) above, optionally followed by hydrolysis treatment to re-generatethe free hydroxyl group of formula (II).

Compounds of formula (XI) may be prepared from the correspondingpiperazine or diazepane by analogous procedures to those described inprocesses (b), (c), (d) and (e) above.

Compounds of formula (XI) wherein Z represents a bond may be prepared byreacting a compound of formula R¹-L⁶ (wherein R¹ is as defined above andL⁶ represents a suitable leaving group, eg. a bromine atom) with acompound of formula (XII), such as 1-BOC-piperazine, in the presence ofa palladium catalyst, such as tris(dibenzylideneacetone) dipalladium,and a ligand such as2-cyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl, in an inertsolvent such as tetrahydrofuran and in the presence of a base such aslithium bis(trimethylsilyl)amide in an inert atmosphere (nitrogen) andat elevated temperature such as 80° C., according to the procedure ofBuchwald, Organic Letters, 2002, 4, 2885-2888.

Compounds of formula (V), (VI), (VIII), (IX), (XII) and (XIII) areeither known or may be prepared in accordance with known procedures.

Certain compounds of formula (I), and their pharmaceutically acceptablesalts have also been found to have affinity for the histamine H1receptor.

Histamine H1 receptors are widely distributed throughout the CNS andperiphery, and are involved in wakefulness and acute inflammatoryprocesses [Hill et al, Pharmacol. Rev. 49:253-278 (1997)]. Seasonalallergic rhinitis, and other allergic conditions, are associated withthe release of histamine from mast cells. The activation of H1 receptorsin blood vessels and nerve endings are responsible for many of thesymptoms of allergic rhinitis, which include itching, sneezing, and theproduction of watery rhinorrhea. Antihistamine compounds, i.e. drugswhich are selective H1 receptor antagonists such as chlorphenyramine andcetirizine, are effective in treating the itching, sneezing andrhinorrhea associated with allergic rhinitis, but are not very effectivein treating the nasal congestion symptoms [Aaronson, Ann. Allergy,67:541-547, (1991)].

H3 receptor agonists are known to inhibit the effect of sympatheticnerve activation on vascular tone in porcine nasal mucosa [Varty & Hey.Eur. J. Pharmacol., 452:339-345, (2002)]. In vivo, H3 receptor agonistsinhibit the decrease in nasal airway resistance produced by sympatheticnerve activation [Hey et al, Arzneim-Forsch Drug Res., 48:881-888(1998)]. Furthermore, H3 receptor antagonists in combination withhistamine H1 receptor antagonists reverse the effects of mast cellactivation on nasal airway resistance and nasal cavity volume, an indexof nasal congestion [McLeod et al, Am. J. Rhinol., 13: 391-399, (1999)].A combined histamine H1 and H3 receptor antagonist, such as the seriesdescribed herein, would be effective in the treatment of both the nasalcongestion and the sneezing, itching and rhinorrhea associated with bothseasonal and perennial allergic rhinitis.

Therefore, examples of disease states in which dual histamine H1 and H3antagonists have potentially beneficial anti-inflammatory effectsinclude diseases of the respiratory tract such as asthma (includingallergic and non-allergic), allergic rhinitis, sinusitis, bronchitis(including chronic bronchitis), bronchiectasis, chronic obstructivepulmonary disease (COPD) and cystic fibrosis.

Other examples of disease states in which dual histamine H1 and H3antagonists have potentially beneficial effects include diseases of thegastrointestinal tract such as intestinal inflammatory diseasesincluding inflammatory bowel disease (e.g. Crohn's disease or ulcerativecolitis) and intestinal inflammatory diseases secondary to radiationexposure or allergen exposure.

Dual histamine H1 and H3 antagonists of the present invention may alsobe of use in the treatment of sleep/wake disorders, arousal/vigilancedisorders, migraine, dementia, mild cognitive impairment (pre-dementia),cognitive dysfunction, Alzheimer's disease, epilepsy, narcolepsy, eatingdisorders, motion sickness, vertigo, attention deficit hyperactivitydisorders, learning disorders, memory retention disorders,schizophrenia, depression, manic disorders, bipolar disorders anddiabetes.

Diseases of principal interest for a dual histamine H1 and H3 antagonistinclude asthma, COPD and inflammatory diseases of the upper respiratorytract involving seasonal and perennial allergic rhinitis, non-allergicrhinitis, and the specific symptoms associated with these diseasesincluding nasal congestion, rhinorrhoea, sneezing, cough and itching(pruritis) of eyes, ears, nose and throat. Other diseases of principalinterest include cough, chronic urticaria, allergic conjunctivitis,nasal polyposis, sinusitis, psoriasis, eczema and allergic dermatoses(including urticaria, atopic dermatitis, contact dermatitis, drug rashesand insect bites).

Diseases of principal interest include asthma, COPD, cognitive disordersand inflammatory diseases of the upper respiratory tract involvingseasonal and perennial rhinitis. Preferred diseases of principalinterest include asthma, cognitive disorders and inflammatory diseasesof the upper respiratory tract involving seasonal and perennialrhinitis. Further diseases also of principal interest includeinflammatory diseases of the gastrointestinal tract such as inflammatorybowel disease.

Thus the invention also provides a dual histamine H1 and H3 antagonistcompound of formula (I) or a pharmaceutically acceptable salt thereof,for use as a therapeutic substance in the treatment or prophylaxis ofthe above disorders, in particular allergic rhinitis.

Preferred dual histamine H1 and H3 antagonist compounds of formula (I)are those wherein:

R¹ represents aryl (eg. phenyl, naphthyl or tetrahydronaphthyl) orheteroaryl (eg. benzofuranyl, indolyl or quinolinyl);R¹ is optionally substituted by one or more (eg. 1, 2 or 3): halogen(eg. chlorine, fluorine or bromine); trifluoromethyl; —C₁₋₆ alkyl (eg.methyl, ethyl, isopropyl, propyl or t-butyl) optionally substituted byCOOR¹⁵ (eg. COOEt); —C₁₋₆ alkoxy (eg. methoxy) optionally substituted byCOOR¹⁵ (eg. COOMe); C₁₋₆ alkenyl (eg. ethenyl); NR¹⁵R¹⁶ (eg. N(Me)₂); orC₁₋₆ alkylthio (eg. —S-ethyl) groups;Z is a bond or CO;m is 0 or 2;n is 0;r is 0;p is 1.R³ represents —(CH₂)_(q)—NR¹¹R¹²;q represents 3; andNR¹¹R¹² represents pyrrolidinyl, piperidinyl, azepanyl or azocanyloptionally substituted by one or more C₁₋₆ alkyl (eg. methyl or ethyl),more preferably piperidinyl substituted by one or two methyl or ethylgroups.

The invention further provides a method of treatment or prophylaxis ofthe above disorders, in mammals including humans, which comprisesadministering to the sufferer a therapeutically effective amount of acompound of formula (I) or a pharmaceutically acceptable salt thereof.

In another aspect, the invention provides the use of a compound offormula (I) or a pharmaceutically acceptable salt thereof in themanufacture of a medicament for use in the treatment of the abovedisorders.

When used in therapy, the compounds of formula (I) are usuallyformulated in a standard pharmaceutical composition. Such compositionscan be prepared using standard procedures.

Thus, the present invention further provides a pharmaceuticalcomposition for use in the treatment of the above disorders whichcomprises the compound of formula (I) or a pharmaceutically acceptablesalt thereof and a pharmaceutically acceptable carrier.

The present invention further provides a pharmaceutical compositionwhich comprises the compound of formula (I) or a pharmaceuticallyacceptable salt thereof and a pharmaceutically acceptable carrier.

The pharmaceutical compositions according to the invention may also beused in combination with other therapeutic agents, for exampleanti-inflammatory agents (such as corticosteroids (e.g. fluticasonepropionate, beclomethasone dipropionate, mometasone furoate,triamcinolone acetonide or budesonide) or NSAIDs (eg. sodiumcromoglycate, nedocromil sodium, PDE-4 inhibitors, leukotrieneantagonists, lipoxygenase inhibitors, chemokine antagonists (e.g CCR3,CCR1, CCR2, CXCR1, CXCR2), iNOS inhibitors, tryptase and elastaseinhibitors, beta-2 integrin antagonists and adenosine 2a agonists)) orbeta adrenergic agents (such as salmeterol, salbutamol, formoterol,fenoterol or terbutaline and salts thereof), or sympathomimetics (e.gpseudoephedrine or oxymetazoline), or other antagonists at the histaminereceptor (e.g H4), or cholinesterase inhibitors, or cholinergicantagonists, or antiinfective agents (eg. antibiotics, antivirals).

A pharmaceutical composition of the invention, which may be prepared byadmixture, suitably at ambient temperature and atmospheric pressure, isusually adapted for oral, topical, parenteral or rectal administrationand, as such, may be in the form of tablets, capsules, oral liquidpreparations, powders, granules, lozenges, reconstitutable powders,injectable or infusible solutions or suspensions or suppositories.Orally administrable compositions are generally preferred.

Tablets and capsules for oral administration may be in unit dose form,and may contain conventional excipients, such as binding agents,fillers, tabletting lubricants, disintegrants and acceptable wettingagents. The tablets may be coated according to methods well known innormal pharmaceutical practice.

Oral liquid preparations may be in the form of, for example, aqueous oroily suspension, solutions, emulsions, syrups or elixirs, or may be inthe form of a dry product for reconstitution with water or othersuitable vehicle before use. Such liquid preparations may containconventional additives such as suspending agents, emulsifying agents,non-aqueous vehicles (which may include edible oils), preservatives,and, if desired, conventional flavourings or colorants.

For parenteral administration, fluid unit dosage forms are preparedutilising a compound of the invention or pharmaceutically acceptablesalt thereof and a sterile vehicle. The compound, depending on thevehicle and concentration used, can be either suspended or dissolved inthe vehicle. In preparing solutions, the compound can be dissolved forinjection and filter sterilised before filling into a suitable vial orampoule and sealing. Advantageously, adjuvants such as a localanaesthetic, preservatives and buffering agents are dissolved in thevehicle. To enhance the stability, the composition can be frozen afterfilling into the vial and the water removed under vacuum. Parenteralsuspensions are prepared in substantially the same manner, except thatthe compound is suspended in the vehicle instead of being dissolved, andsterilisation cannot be accomplished by filtration. The compound can besterilised by exposure to ethylene oxide before suspension in a sterilevehicle. Advantageously, a surfactant or wetting agent is included inthe composition to facilitate uniform distribution of the compound.

The composition may contain from 0.1% to 99% by weight, preferably from10 to 60% by weight, of the active material, depending on the method ofadministration. The dose of the compound used in the treatment of theaforementioned disorders will vary in the usual way with the seriousnessof the disorders, the weight of the sufferer, and other similar factors.However, as a general guide suitable unit doses may be 0.05 to 1000 mg,more suitably 1.0 to 200 mg, and such unit doses may be administeredmore than once a day, for example two or three a day. Such therapy mayextend for a number of weeks or months.

The following Descriptions and Examples illustrate the preparation ofcompounds of the invention.

Description 14-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-piperazine-1-carboxylic acidtert-butyl ester (D1)

To a solution of 4-(3-(piperidin-1-yl)propoxy)benzaldehyde (WO 02/12214A2) (1.90 g, 7.68 mmol) in dichloromethane (25 ml) was added 1-N tertbutoxy carbonyl piperazine (1.57 g, 8.45 mmol) followed by acetic acid(1 ml), and the reaction stirred for 1 hour at room temperature, thentreated with sodium triacetoxy borohydride (2 g, 9.61 mmol) and stirredfor 16 hours at room temperature. The reaction was then diluted withsaturated sodium bicarbonate solution and extracted withdichloromethane. The dichloromethane was then washed sequentially withwater and brine, dried over anhydrous sodium sulfate and evaporated invacuo to yield a residue which was purified using silica gelchromatography eluting with a mixture of 0.880ammonia:methanol:dichloromethane (0.5:4.5:95) to afford the titlecompound (1.586 g, 50%); MS (ES+), m/e 418 [M+H]⁺.

Description 2 1-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-piperazinetrihydrochloride (D2)

To a solution of4-[4-(3-piperidin-1-yl-propoxy)-benzyl]-piperazine-1-carboxylic acidtert-butyl ester (D1) (1.576 g, 3.76 mmol) in a (1:1) mixture ofdichloromethane and methanol (20 ml) was added a 1M solution of hydrogenchloride in diethyl ether (20 ml) and the reaction stirred for 5 hoursat room temperature. The solvent was then evaporated in vacuo and theresulting residue triturated with diethyl ether to afford the titlecompound (1.5 g, 93%); MS (ES+), m/e 318 [M+H]⁺.

Description 34-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-[1,4]diazepane-1-carboxylic acidtert-butyl ester (D3)

The title compound (D3) was prepared from [1,4]diazepane-1-carboxylicacid tert-butyl ester using the method of Description 1 (D1).

MS (ES+) m/e 432 [M+H]⁺.

Description 4 1-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-[1,4]diazepane(D4)

4-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-[1,4]diazepane-1-carboxylic acidtert-butyl ester (D3) (2.27 g, 5.27 mmol) was dissolved indichloromethane (10 ml), treated with trifluoroacetic acid (5 ml) andstirred at room temperature under argon for 2 hours. The solvent wasremoved in vacuo and the residue dissolved in methanol and passed downan SCX column (10 g) eluting with methanol followed by 0.88ammonia/methanol (1:9). The basic fractions were combined andconcentrated in vacuo to afford the title compound (1.57 g).

MS (ES+) m/e 332 [M+H]⁺.

Description 5 4-(4-Formyl-phenoxy)-piperidine-1-carboxylic acidtert-butyl ester (D5)

4-Hydroxybenzaldehyde (2.0 g, 16.4 mmol) was dissolved intetrahydrofuran (20 ml) and treated with4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (4.1 g, 20.5mmol) and triphenylphosphine (5.4 g, 20.5 mmol). The mixture was cooledin an ice bath, treated with diethyl azodicarboxylate (3.2 ml, 20.5mmol) and allowed to stir at room temperature for 36 hours. The reactionmixture was diluted with ethyl acetate, washed with sodium hydroxidesolution (2M), sodium bicarbonate solution and brine. The organic layerwas dried under magnesium sulphate, filtered and the solvent removed invacuo. The title compound (1.85 g) was obtained by column chromatographyeluting with ethyl acetate/hexane (1:4).

¹H NMR (CDCl3) δ 9.88 (1H, s), 7.85-7.82 (2H, d), 7.02-6.99 (2H, d),4.65-4.59 (1H, m), 3.74-3.65 (2H, m), 3.43-3.33 (2H, m), 2.04-1.92 (2H,m), 1.82-1.77 (2H, m), 1.47 (9H, s).

Description 6 4-(4-piperazin-1-ylmethyl-phenoxy)-piperidine-1-carboxylicacid tert-butyl ester (D6)

The title compound (D6) was prepared from4-(4-formyl-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (D5)and piperazine using the method described in Description 1 (D1).

MS (ES+) m/e 376 [M+H]⁺.

Description 74-{4-[4-(1-Phenyl-methanoyl)-piperazin-1-ylmethyl]-phenoxy}-piperidine-1-carboxylicacid tert-butyl ester (D7)

The title compound (D7) was prepared from4-(4-piperazin-1-ylmethyl-phenoxy)-piperidine-1-carboxylic acidtert-butyl ester (D6) and benzoyl chloride using the method described inExample 24 (E24). MS(ES+) m/e 480 [M+H]⁺.

Description 8 4-(4-Hydroxy-phenyl)-piperazine-1-carboxylic acidtert-butyl ester (D8)

Di-tert-butyl dicarbonate (10.1 g; 1.1 eq) was added portion wise to4-piperazin-1-yl-phenol (Chem. Pharm. Bull. 49(10), 1314 (2001)) (7.5 g;42.1 mM) and triethylamine (6.4 ml; 1.1 eq) in dichloromethane (150 ml).The resulting mixture was stirred at room temperature for 18 hours

The reaction was washed with water (2×100 ml), dried (sodium sulphate)and the solvent removed by evaporation in vacuo. The residue waspurified by column chromatography on silica eluting with 4-1hexane-ethyl acetate to afford the title compound as an off-white solid(4.71 g)

MS (ES+) m/e 279 [M+H]⁺.

Description 9 4-[4-(3-Chloro-propoxy)-phenyl]-piperazine-1-carboxylicacid tert-butyl ester (D9)

A mixture of 4-(4-hydroxy-phenyl)-piperazine-1-carboxylic acidtert-butyl ester (D8) (4.0 g; 14.4 mM), 1-bromo-3-chloro propane (1.70ml; 1.2 eq) and potassium carbonate (4.0 g; 2 eq) in butan-2-one (100ml) was heated at reflux for 18 hours. The mixture was allowed to coolto room temperature, filtered and evaporated. The residue was purifiedby column chromatography on silica eluting with 4-1 hexane-ethyl acetateto afford the title compound as a colourless viscous oil (3.8 g)

MS (ES+) m/e 355 [M+H]⁺.

Description 104-[4-(3-Piperidin-1-yl-propoxy)-phenyl]-piperazine-1-carboxylic acidtert-butyl ester (D10)

A mixture of 4-[4-(3-chloro-propoxy)-phenyl]-piperazine-1-carboxylicacid tert-butyl ester (D9) (4.0 g; 11.3 mM), piperidine (2.23 ml; 2 eq),potassium carbonate (3.73 g; 2.4 eq) and potassium iodide (3.74 g; 2 eq)in butan-2-one (100 ml) was heated at reflux for 3 days. The mixture wasallowed to cool to room temperature, filtered and evaporated to give thetitle compound as a pale yellow solid (4.6 g)

MS (ES+) m/e 404 [M+H]⁺.

Description 11 1-[4-(3-Piperidin-1-yl-propoxy)-phenyl]-piperazine (D11)

A solution of4-[4-(3-piperidin-1-yl-propoxy)-phenyl]-piperazine-1-carboxylic acidtert-butyl ester (D10) (1.0 g; 2.48 mM) in trifluoroacetic acid (5 ml)was stirred at room temperature for 60 minutes. The resulting mixturewas purified on an SCX ion exchange cartridge to afford the titlecompound as a colourless crystalline solid (0.76 g)

MS (ES+) m/e 304 [M+H]⁺.

Description 12 4-(3-Hydroxy-phenyl)-piperazine-1-carboxylic acidtert-butyl ester (D12)

Prepared from 3-piperazin-1-yl-phenol (Chem. Pharm. Bull. 49(10), 1314(2001)) using the same method described in Description 8 (D8).

MS (ES+) m/e 279 [M+H]⁺.

Description 13 4-[3-(3-Chloro-propoxy)-phenyl]-piperazine-1-carboxylicacid tert-butyl ester (D13)

Prepared from 4-(3-hydroxy-phenyl)-piperazine-1-carboxylic acidtert-butyl ester (D12) using the same method described in Description 9(D9).

MS (ES+) m/e 355 [M+H]⁺.

Description 144-[3-(3-Piperidin-1-yl-propoxy)-phenyl]-piperazine-1-carboxylic acidtert-butyl ester (D14)

Prepared from 4-[3-(3-chloro-propoxy)-phenyl]-piperazine-1-carboxylicacid tert-butyl ester (D13) using the same method described inDescription 10 (D10).

MS (ES+) m/e 404 [M+H]⁺.

Description 15 1-[3-(3-Piperidin-1-yl-propoxy)-phenyl]-piperazine (D15)

Prepared from4-[3-(3-piperidin-1-yl-propoxy)-phenyl]piperazine-1-carboxylic acidtert-butyl ester (D14) using the same method described in Description 11(D11).

MS (ES+) m/e 304 [M+H]⁺.

Description 16 4-Bromo-1-methyl-1H-indole (D16)

A solution of 4-bromo-1H-indole (6.7 g) in tetrahydrofuran (75 ml) wastreated with sodium hydride (1.24 g) and stirred for 0.5 h at roomtemperature. The resulting suspension was treated with a solution ofiodomethane (2.34 ml) in tetrahydrofuran (35 ml) at 0° C. and allowed towarm to room temperature over 1 h, whilst stirring. The reaction mixturewas poured onto water and partitioned between dichloromethane and water.The organic phase was dried over (MgSO₄) and concentrated in vacuo toafford the title compound (7.2 g). TLC Silica (cyclohexane-ethyl acetate[1:1]), Rf=0.55.

Description 17 4-Bromo-1-methyl-1H-indole-3-carboxylic acid (D17)

A solution of 4-bromo-1-methyl-1H-indole (D16) (7.0 g) intetrahydrofuran (50 ml) was treated with a solution of trifluoroaceticanhydride (5.65 ml) in tetrahydrofuran (20 ml) at 0° C. The reactionmixture was allowed to warm to room temperature over 6 h, whilststirring. The reaction mixture was concentrated in vacuo and thenre-suspended in ethanol (25 ml). The solution was treated with 5N sodiumhydroxide solution (50 ml) and heated under reflux for 18 h. Thereaction mixture was washed with diethyl ether and the aqueous phaseacidified with 5N hydrochloric acid solution. The precipitate wasfiltered, washed with water and concentrated in vacuo to afford thetitle compound (4.88 g). TLC, Silica (cyclohexane-ethyl acetate-aceticacid [3:1:0.1]), Rf=0.35.

Descriptions 18-23

Descriptions 18-23 were prepared using analogous methods to Example 76bby substituting 2-methylpiperidine with the appropriate amine.

Mass Ion Description Structure RT (min) (M + H)⁺ 18

1.64 332 19

0.65 304 20

1.77 346 21

1.45 318 22

1.57 332 23

1.61 318

Descriptions 24-32

Descriptions 24-32 were prepared by analogous methods to those indicatedin the below table:

Prepared Descrip- analogously RT tion Name to (min) 24 1,1-Dimethylethyl4-(2-naphthalenyl)- E229a from 3.74 1-piperazinecarboxylate knownstarting materials 25 1,1-Dimethylethyl 4-(4-quinolinyl)-1- E229a from2.18 piperazinecarboxylate and 1,1- known & dimethylethyl4-(3-quinolinyl)-1- starting 3.02 piperazinecarboxylate (1:1) materials26 1-(2-Naphthalenyl)piperazine E229b from 2.00 known starting materials27 4-(1-Piperazinyl)quinoline and 3-(1- E229b from 1.18piperazinyl)quinoline (1:1) D25 28 3-{[4-(2-Naphthalenyl)-1- E229c from2.39 piperazinyl]methyl}phenol D24 29 3-{[4-(1-Naphthalenyl)-1- E229cfrom 2.41 piperazinyl]methyl}phenol D26 30 4-{[4-(8-Quinolinyl)-1- E229cfrom 1.78 piperazinyl]methyl}phenol E229b 31 4-{[4-(4-Quinolinyl)-1-E229c from 1.91 piperazinyl]methyl}phenol and 3-{[4- D27(3-quinolinyl)-1- piperazinyl]methyl}phenol (1:1) 324-{[4-(1-Naphthalenyl)-1- E229c from 2.46 piperazinyl]methyl}phenol D26

Descriptions 33-42

Descriptions 33-42 were prepared by analogous methods to those indicatedin the below table:

Prepared Descrip- analogously RT tion Name to (min) 332-Methyl-4-[4-(2-{4- E237a from 2.20 [(phenylmethyl)oxy]phenyl}ethyl)-1-known piperazinyl]quinoline starting materials 34 2-Methyl-4-[4-(2-{3-E237a from 2.11 [(phenylmethyl)oxy]phenyl}ethyl)-1- knownpiperazinyl]quinoline starting materials 35 1-(1-Naphthalenyl)-4-(2-{4-E237a from 2.91 [(phenylmethyl)oxy]phenyl}ethyl) known piperazinestarting materials 36 1-(1-Naphthalenyl)-4-(2-{3- E237a from 2.82[(phenylmethyl)oxy]phenyl}ethyl) known piperazine starting materials 371-Phenyl-4-(2-{4- E237a from 2.55 [(phenylmethyl)oxy]phenyl}ethyl) knownpiperazine starting materials 38 4-{2-[4-(2-Methyl-4-quinolinyl)-1-E237b from 1.69 piperazinyl]ethyl}phenol D33 393-{2-[4-(2-Methyl-4-quinolinyl)-1- E237b from 4.56piperazinyl]ethyl}phenol D34 40 4-{2-[4-(1-Naphthalenyl)-1- E237b from2.28 piperazinyl]ethyl}phenol D35 41 3-{2-[4-(1-Naphthalenyl)-1- E237bfrom 2.32 piperazinyl]ethyl}phenol D36 42 4-[2-(4-Phenyl-1- E237b from2.02 piperazinyl)ethyl]phenol D37

Description 43 3-Bromo-4-ethyl-benzoic acid (D43)

To a mixture of conc. HNO₃ (66 mL), glacial AcOH (300 mL) and water (50mL), 4-ethyl-benzoic acid (15 g) was added, stirring vigorously, beforetreating with bromine (5.67 mL). Finally a solution of AgNO₃ (16.97 g)in water (50 mL) was added dropwise and the mixture was stirredvigorously for 2 h. The precipitate was collected by filtration, washedwell with water, before being extracted with hot, saturated K₂CO₃solution, and then treated with charcoal. The hot solution was filteredthrough kieselguhr and the solution was acidified to pH1 using conc.HCl. The resulting white precipitate was collected by filtration anddried in the vacuum oven overnight at 60° C. to afford the titlecompound (19.46 g).

NMR (CDCl₃) δ 1.26 (3H, t), 2.83 (2H, q), 7.34 (1H, d), 7.97 (1H, dd),8.27 (1H, dd)

Description 44 Methyl 3-bromo-4-ethyl-benzoate (D44)

3-Bromo-4-ethyl-benzoic acid (D43) (19.40 g) was dissolved in MeOH (200mL) and then treated with conc. H₂SO₄ (1 mL). The mixture was heated atreflux overnight, and then concentrated under reduced pressure. Theresidue was partitioned between EtOAc and saturated aqueous NaHCO₃solution, extracting again with EtOAc. The combined extracts were thenwashed with brine, dried (MgSO₄). The solvent was evaporated in vacuo toafford the title compound (15.8 g). ¹H NMR (CDCl₃) δ 1.24 (3H, t), 2.79(2H, q), 3.91 (3H, s), 7.29 (1H, d), 7.89 (1H, dd), 8.19 (1H, d).

Description 45 Methyl 3-cyano-4-ethyl-benzoate (D45)

Methyl 3-bromo-4-ethyl-benzoate (D44) (5 g) in NMP (180 mL) was treatedwith copper (I) cyanide (3.69 g). The mixture was then heated at refluxfor 5 h, under argon. After cooling to 20° C. the reaction mixture wasdiluted with water, then filtered through kieselguhr, washing well withwater and EtOAc. The organic layer was washed with water, brine anddried over MgSO₄. The solvent was evaporated to dryness in vacuo and theresidue was purified by chromatography on silica eluting withEtOAc-Hexane (1:9) to give the title compound (1.9 g) ¹H NMR (CDCl₃) δ1.33 (3H, t), 2.94 (2H, q), 3.94 (3H, s), 7.43 (1H, d), 8.17 (1H, dd),8.28 (1H, d).

Description 46 3-Cyano-4-ethyl benzoic acid (D461

Methyl 3-cyano-4-ethyl-benzoate (D45) (1.92 g) was dissolved in MeOH (50mL) before adding 1M NaOH solution (15.24 mL) and stirring the resultingmixture overnight at room temperature, under argon. The reaction mixturewas diluted with water, and extracted with EtOAc. The aqueous layer wasacidified to pH1 using 2M HCl before extracting with EtOAc. The combinedextracts were washed with brine, dried over MgSO₄ and the solventevaporated to dryness in vacuo to afford the title compound (1.63 g). ¹HNMR (CDCl₃) δ 1.35 (3H, t), 2.97 (2H, q), 7.49 (1H, d), 8.24 (1H, dd),8.36 (1H, d).

Analysis of the Examples was performed as follows:

LCMS was conducted on a Supelcosil LCABZ+PLUS column (3.3 cm×4.6 mm ID)eluting with 0.1% formic acid and 0.01 M ammonium acetate in water(solvent A) and 0.05% formic acid and 5% water in acetonitrile (solventB), using the following elution gradient 0.0-7 min 0% B, 0.7-4.2 min100% B, 4.2-5.3 min 0% B, 5.3-5.5 min 0% B at a flow rate of 3 mL/min.The mass spectra were recorded on a Fisons VG Platform spectrometerusing electrospray positive and negative mode (ES+ve and ES−ve).

Preparative mass directed HPLC was conducted on a Waters FractionLynxsystem comprising of a Waters 600 pump with extended pump heads, Waters2700 autosampler, Waters 996 diode array and Gilson 202 fractioncollector on a 10 cm×2.54 cm ID ABZ+column, eluting with 0.1% formicacid in water (solvent A) and 0.1% formic acid in acetonitrile (solventB), using an appropriate elution gradient, at a flow rate of 20 ml/minand detecting at 200-320 nm at room temperature. Mass spectra wererecorded on Micromass ZMD mass spectrometer using electrospray positiveand negative mode, alternate scans. The software used was MassLynx 3.5with OpenLynx and FractionLynx options.

EXAMPLE 11-Phenyl-1-{4-[4-(3-piperidin-1-yl-propoxy)-benzyl]-piperazin-1-yl}-methanone(E1)

N-Cyclohexylcarbodiimide, N-methyl polystyrene HL (200-400 mesh) 1.8mMol/g (650 mg, 1.172 mmol) was suspended in a (1:1) mixture ofdichloromethane and dimethylformamide and treated sequentially withbenzoic acid (72 mg, 0.58 mmol), 1-hydroxybenzotriazole hydrate (80 mg,0.58 mmol) and stirred for 10 minutes at room temperature. A solution of1-[4-(3-piperidin-1-yl-propoxy)-benzyl]-piperazine trihydrochloride (D2)(125 mg, 0.29 mmol) in dichloromethane (1 ml) and triethylamine (0.13ml, 0.87 mmol) was then added to the reaction and stirred at roomtemperature for 16 hours. After filtration, the filtrate was applied toa Mega Bond elute SCX ion exchange column washing sequentially withwater and methanol, followed by 0.880 ammonia/methanol (1:10) to elutethe crude reaction mixture. Purification by silica gel chromatographyeluting with a mixture of 0.880 ammonia:methanol:dichloromethane(0.5:4.5:95) to afford the title product (95 mg, 77%); MS (ES+), m/e 422[M+H]⁺.

EXAMPLES 2-11

Examples 2-11 (E2-E11) were prepared from Description 2 (D2) using ananalogous method to that described in Example 1 (E1) by substitutingbenzoic acid for the appropriate acid indicated in the table.

Example Acid Mass Spectrum 1-Benzo[1,3]dioxol-5-yl-1-{4-[4-(3-piperonylic acid MS (ES+) m/epiperidin-1-yl-propoxy)-benzyl]-piperazin-1- 466 [M + H]⁺ yl}-methanone(E2) 1-Naphthalen-2-yl-1-{4-[4-(3-piperidin-1-yl- 2-naphthoic acid MS(ES+) m/e propoxy)-benzyl]-piperazin-1-yl}- 472 [M + H]⁺ methanone (E3)1-(3,5-Dichloro-phenyl)-1-{4-[4-(3- 3,5- MS (ES+) m/epiperidin-1-yl-propoxy)-benzyl]-piperazin-1- dichlorobenzoic 491/493[M + H]⁺ yl}-methanone (E4) acid 1-(4-Bromo-3-methyl-phenyl)-1-{4-[4-(3-3-methyl, 4-bromo MS (ES+) m/epiperidin-1-yl-propoxy)-benzyl]-piperazin-1- benzoic acid 515/517 [M +H]⁺ yl}-methanone (E5) 1-(2-Methoxy-phenyl)-1-{4-[4-(3-piperidin-2-methoxy benzoic MS (ES+) m/e 1-yl-propoxy)-benzyl]-piperazin-1-yl}-acid 452 [M + H]⁺ methanone (E6) 1-(3,4-Dichloro-phenyl)-1-{4-[4-(3-3,4-dichloro MS (ES+) m/e piperidin-1-yl-propoxy)-benzyl]-piperazin-1-benzoic acid 491/493/495 yl}-methanone (E7) [M + H]⁺4-(1-{4-[4-(3-Piperidin-1-yl-propoxy)- 4-cyano benzoic MS (ES+) m/ebenzyl]-piperazin-1-yl}-methanoyl)- acid 447 [M + H]⁺ benzonitrile (E8)1-(4-Fluoro-phenyl)-1-{4-[4-(3-piperidin-1- 4-fluoro benzoic MS (ES+)m/e yl-propoxy)-benzyl]-piperazin-1-yl}- acid 440 [M + H]⁺ methanone(E9) 1-(4-Bromo-phenyl)-1-{4-[4-(3-piperidin-1- 4-bromo benzoic MS (ES+)m/e yl-propoxy)-benzyl]-piperazin-1-yl}- acid 500/502 [M + H]⁺ methanone(E10) 1-Benzofuran-2-yl-1-{4-[4-(3-piperidin-1-yl- 2-benzofuran MS (ES+)m/e propoxy)-benzyl]-piperazin-1-yl}- carboxylic acid 462 [M + H]⁺methanone (E11)

EXAMPLE 121-Benzo[1,3]dioxol-5-yl-1-{4-[4-(3-piperidin-1-yl-propoxy)-benzyl]-[1,4]diazepan-1-yl}-methanone(E12)

1-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-[1,4]diazepane (D4) (100 mg,0.30 mmol) was dissolved in dichloromethane (5 ml) and treatedsequentially with benzo[1,3]dioxole-5-carboxylic acid (125 mg, 0.75mmol), 1,3-dicyclohexylcarbodiimide (155 mg, 0.75 mmol) and1-hydroxybenzotriazole hydrate (101 mg, 0.75 mmol). The mixture wasallowed to stir at room temperature under argon for 12 hours, dilutedwith methanol and passed down an SCX ion exchange column (2 g) elutingwith methanol followed by 0.880 ammonia/methanol (1:9). The basicfractions were combined and concentrated in vacuo to afford the titlecompound (127 mg). MS (ES+) m/e 480 [M+H]⁺.

EXAMPLES 13-15

Examples 13-15 (E13-E15) were prepared from Description 4 (D4) using ananalogous method to that described in Example 12 (E12) by substitutingbenzo[1,3]dioxole-5-carboxylic acid for the appropriate acid indicatedin the table.

Example Carboxylic acid Mass Spectrum1-Phenyl-1-{4-[4-(3-piperidin-1-yl-propoxy)- Benzoic acid MS(ES+) m/ebenzyl]-[1,4]diazepan-1-yl}-methanone (E13) 436 [M + H]⁺1-Naphthalen-2-yl-1-{4-[4-(3-piperidin-1-yl-propoxy)- Naphthalene-2-MS(ES+) m/e benzyl]-[1,4]diazepan-1-yl}-methanone (E14) carboxylic acid486 [M + H]⁺ 1-(3,5-Dichloro-phenyl)-1-{4-[4-(3-piperidin-1-yl-3,5-Dichloro-benzoic MS(ES+) m/epropoxy)-benzyl]-[1,4]diazepan-1-yl}-methanone (E15) acid 505 [M + H]⁺

EXAMPLES 16-23

Examples 16-23 (E16-E23) were prepared from Description 4 (D4) using ananalogous method to that described in Example 12 (E12) by substitutingbenzo[1,3]dioxole-5-carboxylic acid for the appropriate acid indicatedin the table followed by further purification by column chromatographyon silica gel eluting with a mixture of 0.880ammonia/methanol/dichloromethane (0.5:4.5:95).

Example Carboxylic acid Mass Spectrum1-(4-Bromo-3-methyl-phenyl)-1-{4-[4-(3-piperidin-1-yl- 4-Bromo-3-methyl-MS(ES+) m/e propoxy)-benzyl]-[1,4]diazepan-1-yl}-methanone (E16) benzoicacid 529 [M + H]⁺1-(2-Methoxy-phenyl)-1-{4-[4-(3-piperidin-1-yl-propoxy)-2-Methoxy-benzoic MS(ES+) m/e benzyl]-[1,4]diazepan-1-yl}-methanone(E17) acid 466 [M + H]⁺ 4-(1-{4-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-4-Cyano-benzoic acid MS(ES+) m/e[1,4]diazepan-1-yl}-methanoyl)-benzonitrile (E18) 461 [M + H]⁺1-(4-Fluoro-phenyl)-1-{4-[4-(3-piperidin-1-yl-propoxy)- 4-Fluoro-benzoicacid MS(ES+) m/e benzyl]-[1,4]diazepan-1-yl}-methanone (E19) 454 [M +H]⁺ 1-(4-Bromo-phenyl)-1-{4-[4-(3-piperidin-1-yl-propoxy)-4-Bromo-benzoic acid MS(ES+) m/e benzyl]-[1,4]diazepan-1-yl}-methanone(E20) 515 [M + H]⁺ 1-Benzofuran-2-yl-1-{4-[4-(3-piperidin-1-yl-propoxy)-Benzofuran-2- MS(ES+) m/e benzyl]-[1,4]diazepan-1-yl}-methanone (E21)carboxylic acid 476 [M + H]⁺1-(3,4-Dichloro-phenyl)-1-{4-[4-(3-piperidin-1-yl- 3,4-Dichloro- MS(ES+)m/e propoxy)-benzyl]-[1,4]diazepan-1-yl}-methanone (E22) benzoic acid505 [M + H]⁺ 1-Cyclopropyl-1 -{4-[4-(3-piperidin-1-yl-propoxy)-Cyclopropane MS(ES+) m/e benzyl]-[1,4]diazepan-1-yl}-methanone (E23)carboxylic acid 400 [M + H]⁺

EXAMPLE 241-Cyclopentyl-1-{4-[4-(3-piperidin-1-yl-propoxy)-benzyl]-[1,4]diazepan-1-yl}-methanone(E24)

1-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-[1,4]diazepane (D4) (100 mg,0.30 mmol) was dissolved in dichloromethane (5 ml), treated withcyclopentyl acid chloride (80 mg, 0.60 mmol), potassium carbonate (83mg, 0.60 mmol) and allowed to stir at room temperature under argon for12 hours. The reaction mixture was diluted with methanol and passed downan SCX column (2 g) eluting with methanol followed by ammonia/methanol(1:9). The basic fractions were combined and concentrated in vacuo toafford the title compound (56 mg).

MS (ES+) m/e 428 [M+H]⁺.

EXAMPLE 251-Benzenesulfonyl-4-[4-(3-piperidin-1-yl-propoxy)-benzyl]-[1,4]diazepane(E25)

1-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-[1,4]diazepane (D4) (100 mg,0.30 mmol) was dissolved in 2-butanone (5 ml), treated with benzenesulfonyl chloride (57 mg, 0.32 mmol) and allowed to stir at roomtemperature under argon for 2 hours. The reaction mixture was dilutedwith methanol and passed down an SCX column (2 g) eluting with methanolfollowed by ammonia/methanol (1:9). The basic fractions were combinedand concentrated in vacuo to afford the title compound (91 mg). MS (ES+)m/e 472 [M+H]⁺.

EXAMPLES 26-28

Examples 26-28 (E26-E28) were prepared from Description 4 (D4) using ananalogous method to that described in Example 25 (E25) by substitutingbenzenesulfonyl chloride for the appropriate sulfonyl chloride indicatedin the table.

Example Sulfonyl Chloride Mass Spectrum1-(Naphthalene-2-sulfonyl)-4-[4-(3- Naphthalene-2- MS(ES+) m/epiperidin-1-yl-propoxy)-benzyl]- sulfonyl chloride 522 [M + H]⁺[1,4]diazepane (E26) 1-(4-Fluoro-benzenesulfonyl)-4-[4-(3- 4-Fluoro-MS(ES+) m/e piperidin-1-yl-propoxy)-benzyl]- benzenesulfonyl 490 [M +H]⁺ [1,4]diazepane (E27) chloride 1-(4-Bromo-benzenesulfonyl)-4-[4-(3-4-Bromo- MS(ES+) m/e piperidin-1-yl-propoxy)-benzyl]- benzenesulfonyl552 [M + H]⁺ [1,4]diazepane (E28) chloride

EXAMPLES 29-31

Examples 29-31 (E29-E31) were prepared from Description 4 (D4) using ananalogous method to that described in Example 25 (E25) by substitutingbenzenesulfonyl chloride for the appropriate sulfonyl chloride indicatedin the table followed by further purification by column chromatographyon silica gel eluting with a mixture of 0.880ammonia/methanol/dichloromethane (0.5:4.5:95).

Example Sulfonyl Chloride Mass Spectrum1-(3,5-Dichloro-benzenesulfonyl)- 3,5-Dichloro- MS(ES+) m/e4-[4-(3-piperidin-1-yl-propoxy)- benzenesulfonyl 540 [M + H]⁺benzyl]-[1,4]diazepane (E29) chloride 1-(3,4-Dichloro-benzenesulfonyl)-3,4-Dichloro- MS(ES+) m/e 4-[4-(3-piperidin-1-yl-propoxy)-benzenesulfonyl 540 [M + H]⁺ benzyl]-[1,4]diazepane (E30) chloride4-{4-[4-(3-Piperidin-1-yl-propoxy)- 4-Cyano- MS(ES+) m/ebenzyl]-[1,4]diazepane-1- benzenesulfonyl 497 [M + H]⁺sulfonyl}-benzonitrile (E31) chloride

EXAMPLE 321-Phenyl-1-{4-[4-(piperidin-4-yloxy)-benzyl]-piperazin-1-yl}-methanone(E32)

The title compound (E32) was prepared from4-{4-[4-(1-phenyl-methanoyl)-piperazin-1-ylmethyl]-phenoxy}-piperidine-1-carboxylicacid tert-butyl ester (D7) using the method described in Description 4(D4). MS (ES+) m/e 380 [M+H]⁺.

EXAMPLE 331-{4-[4-(1-Isopropyl-piperidin-4-yloxy)-benzyl]-piperazin-1-yl}-1-phenyl-methanone(E33)

The title compound (E33) was prepared from1-phenyl-1-{4-[4-(piperidin-4-yloxy)-benzyl]-piperazin-1-yl}-methanone(E32) and acetone using the method described in Description 1 (D1). MS(ES+) m/e 422 [M+H]⁺.

EXAMPLE 341-(4-{4-[1-(2-Methoxy-ethyl)-piperidin-4-yloxy]-benzyl}-piperazin-1-yl)-1-phenyl-methanone(E34)

1-Phenyl-1-{4-[4-(piperidin-4-yloxy)-benzyl]-piperazin-1-yl}-methanone(E32) (150 mg, 0.40 mmol) was dissolved in 2-butanone and treated with1-chloro-2-methoxy-ethane (0.08 ml, 0.80 mmol), potassium carbonate (132mg, 0.96 mmol) and potassium iodide (159 mg, 0.96 mmol). The reactionmixture was heated under reflux for 24 hours. The mixture was allowed tocool to room temperature, acidified by the addition of glacial aceticacid and passed down an SCX ion exchange column (2 g) eluting withmethanol followed by ammonia/methanol (1:9). The basic fractions werecombined and concentrated in vacuo to afford the title compound (76 mg).MS (ES+) m/e 438 [M+H]⁺.

EXAMPLES 35-37

Examples 35-37 (E35-E37) were prepared in accordance with the followinggeneral synthesis:

The appropriate acid chloride (1.1 eq) was added to a mixture of1-[4-(3-piperidin-1-yl-propoxy)-phenyl]-piperazine (D11) (100 mg; 0.33mM) and potassium carbonate (55 mg; 1.5 eq) in butan-2-one (2 ml). Theresulting mixtures were stirred at room temperature for 3 hours and thenpurified on SCX ion exchange cartridges to afford the title compounds.

Example Acid Chloride Mass Spectrum 1-Cyclopropyl-1-{4-[4-(3-piperidin-Cyclopropane MS (ES+) m/e 1-yl-propoxy)-phenyl]-piperazin-1- carbonylchloride 372 [M + H]⁺. yl}-methanone (E35)1-Phenyl-1-{4-[4-(3-piperidin-1-yl- Benzoyl chloride MS (ES+) m/epropoxy)-phenyl]-piperazin-1-yl}- 408 [M + H]⁺. methanone (E36)1-(3,4-Dichloro-phenyl)-1-{4-[4-(3- 3,4- MS (ES+) m/epiperidin-1-yl-propoxy)-phenyl]- Dichlorobenzoyl 477 [M + H]⁺.piperazin-1-yl}-methanone (E37) chloride

EXAMPLES 38-39

Examples 38-39 (E38-E39) were prepared from1-[3-(3-piperidin-1-yl-propoxy)-phenyl]-piperazine (D15) using the sameprocedure as described in Examples 36 and 37, respectively.

Example Mass Spectrum 1-Phenyl-1-{4-[3-(3-piperidin-1-yl-propoxy)- MS(ES+)m/e phenyl]-piperazin-1-yl}-methanone (E38) 408 [M + H]⁺.1-(3,4-Dichloro-phenyl)-1-{4-[3-(3-piperidin-1-yl- MS (ES+) m/epropoxy)-phenyl]-piperazin-1-yl}-methanone 477 [M + H]⁺. (E39)

EXAMPLES 40-42

Examples 40-42 (E40-E42) were prepared in accordance with the followinggeneral synthesis:

The appropriate sulphonyl chloride (1.1 eq) was added to a mixture of1-[4-(3-piperidin-1-yl-propoxy)-phenyl]-piperazine (D11) (100 mg; 0.33mM) and potassium carbonate (55 mg; 1.5 eq) in butan-2-one (2 ml). Theresulting mixtures were stirred at room temperature for 3 hours and thenpurified on SCX ion exchange cartridges to afford the title compounds.

Example Sulfonyl Chloride Mass Spectrum1-Methanesulphonyl-4-[4-(3-piperidin-1-yl- Methane sulfonyl MS (ES+) m/epropoxy)-phenyl]-piperazine (E40) chloride 382 [M + H]⁺.1-Benzenesulphonyl-4-[4-(3-piperidin-1-yl- Benzene sulfonyl MS (ES+) m/epropoxy)-phenyl]-piperazine (E41) chloride 444 [M + H]⁺. 1-(3,4-Dichlorobenzenesulphonyl)-4-[4-(3- 3,4- MS (ES+) m/epiperidin-1-yl-propoxy)-phenyl]-piperazine Dichlorobenzene 513 [M + H]⁺.(E42) sulfonyl chloride

EXAMPLES 43-45

Examples 43-45 (E43-E45) were prepared from1-[3-(3-piperidin-1-yl-propoxy)-phenyl]-piperazine (D15) using the sameprocedure as described in Examples 40, 41 and 42, respectively.

Example Mass Spectrum 1-Methanesulphonyl-4-[3-(3-piperidin-1-yl- MS(ES+) m/e propoxy)-phenyl]-piperazine (E43) 382 [M + H]⁺.1-Benzenesulphonyl-4-[3-(3-piperidin-1-yl- MS (ES+) m/epropoxy)-phenyl]-piperazine (E44) 444 [M + H]⁺. 1-(3,4-Dichlorobenzenesulphonyl)-4-[3-(3- MS (ES+) m/epiperidin-1-yl-propoxy)-phenyl]-piperazine (E45) 513 [M + H]⁺.

EXAMPLES 46-47

Examples 46-47 (E46-E47) were prepared in accordance with the followinggeneral synthesis:

The appropriate isocyanate (1.1 eq) was added to1-[4-(3-piperidin-1-yl-propoxy)-phenyl]-piperazine (D11) (100 mg; 0.33mM) in butan-2-one (2 ml). The resulting mixtures were stirred at roomtemperature for 3 hours and then purified on SCX ion exchange cartridgesto afford the title compounds.

Example Isocyanate Mass Spectrum 4-[4-(3-Piperidin-1-yl-propoxy)-Isocyanatobenzene MS (ES+) m/e phenyl] piperazine-1-carboxylic acid 423[M + H]⁺. phenylamide (E46) 4-[4-(3-Piperidin-1-yl-propoxy)-3,4-Dichloro MS (ES+) m/e phenyl] piperazine-1-carboxylic acidisocyanato benzene 492 [M + H]⁺. (3,4-dichloro-phenyl)-amide (E47)

EXAMPLE 484-[4-(3-Piperidin-1-yl-propoxy)-phenyl]piperazine-1-carboxylic acidcyclopropylamide (E48)

To a solution of 1-[4-(3-piperidin-1-yl-propoxy)-phenyl]-piperazine(D11) (150 mg; 0.49 mM) in dry dichloromethane (3 ml) was added dropwise a 20% solution of phosgene in toluene (0.5 ml; ˜2 eq) and theresulting mixture stirred for 1 hour. The solvent was removed byevaporation and the resulting white powder dissolved in drydichloromethane (4 ml). Triethylamine (0.14 ml: 2 eq) was added followedby cyclopropylamine (0.1 ml; 3 eq) and the mixture stirred for 18 hours.The solvent was removed by evaporation in vacuo and the residue purifiedon a silica column eluting with 3% methanol in dichloromethane to affordthe title compound as a white solid (155 mg)

MS (ES+) m/e 387 [M+H]⁺.

EXAMPLES 49-50

Examples 49-50 (E49-E50) were prepared from1-[3-(3-piperidin-1-yl-propoxy)-phenyl]-piperazine (D15) using the sameprocedure as described in Examples 46 and 47, respectively.

Example Mass Spectrum 4-[3-(3-Piperidin-1-yl-propoxy)-phenyl] MS (ES+)m/e piperazine-1-carboxylic acid phenylamide (E49) 423 [M + H]⁺.4-[3-(3-Piperidin-1-yl-propoxy)-phenyl] MS (ES+) m/epiperazine-1-carboxylic acid (3,4-dichloro- 492 [M + H]⁺. phenyl)-amide(E50)

EXAMPLE 511-(3,4-Dichloro-phenyl)-4-[4-(3-Piperidin-1-yl-propoxy)-phenyl]piperazine(E51)

Tris(dibenzylidineacetone) di palladium (0) (5 mol %; 23 mg) was addedto a mixture of 1-[4-(3-piperidin-1-yl-propoxy)-phenyl]-piperazine (D11)(150 mg; 0.49 mmol), 3,4-dichloro bromo benzene (160 mg; 1.2 eq), sodiumtert-butoxide (71 mg; 1.1 eq) and racemic2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (7.5 mol %; 24 mg) in drytoluene (3 ml). The resulting mixture was heated at reflux under argonfor 18 hours. The reaction was allowed to cool to room temperature anddiluted with ethyl acetate (10 ml). The resulting solids were removed byfiltration and the filtrate evaporated in vacuo. The residue waspurified by column chromatography on silica eluting with 3% methanol indichloromethane to afford the title compound as a buff solid (45 mg)

MS (ES+) m/e 448 [M+H]⁺.

EXAMPLE 521-(3,4-Dichloro-phenyl)-4-[3-(3-Piperidin-1-yl-propoxy)-phenyl]piperazine(E52)

The title compound (E52) was prepared from1-[3-(3-piperidin-1-yl-propoxy)-phenyl]-piperazine (D15) using the samemethod as described in Example 51 (E51).

MS (ES+) m/e 448 [M+H]⁺.

EXAMPLE 535-Fluoro-1-methyl-3-{[4-(4-{[3-(1-piperidinyl)propyl]oxy}phenyl)-1-piperazinyl]carbonyl}-1H-indole(E53)

A solution of 5-fluoro-1-methyl-1H-indole-3-carboxylic acid [WO 0071537A1] (35 mg) and 1-(4-{[3-(1-piperidinyl)propyl]oxy}phenyl)piperazine(D11) (50 mg) in dichloromethane (1 ml) was treated withbenzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (94.4mg) and heated in a microwave (CEM™ Discover microwave) at 120° C. for 5min. The reaction mixture was concentrated in vacuo and purified on aSCX cartridge (2 g) eluting with methanol-aqueous ammonia (10:1)followed by mass directed auto preparative HPLC to give the titlecompound (12 mg). LCMS RT=2.49 min, 478 (M+H)⁺

EXAMPLES 54-61

The following compounds were prepared in an analogous manner to theprocess described for E53 from D11 and a known appropriate acid, withthe exception of Example 57 which was prepared from D11 and D17.

Mass ion Example Structure RT (min) (M + H)⁺ 54

2.37 448 450 55

2.26 464 56

2.41 478 57

2.40 539 541 58

2.32 474 59

2.56 539 541 60

2.54 546 61

2.80 536

EXAMPLE 62(1-Methyl-3-{[4-(4-{[3-(1-piperidinyl)propyl]oxy}phenyl)-1-piperazinyl]carbonyl}-1H-indol-2-yl)aceticacid (E62)

A solution of ethyl(1-methyl-3-{[4-(4-{[3-(1-piperidinyl)propyl]oxy}phenyl)-1-piperazinyl]carbonyl}-1H-indol-2-yl)acetate(E60) [54 mg] in methanol [6 ml] and water [0.8 ml] was treated with 2Nsodium hydroxide [0.46 ml] and was heated under reflux for 2 h. Thereaction mixture was quenched with hydrochloric acid [10 ml] at roomtemperature. The reaction mixture was concentrated in vacuo andpartitioned between ethyl acetate and water. The organic phase was driedand concentrated in vacuo to give the title compound (20 mg). LCMSRT=2.35 min, 518 (M+H)⁺

EXAMPLE 631-(1-Naphthoyl)-4-[4-(3-piperidin-1-ylpropoxy)phenyl]piperazinetrifluoroacetate (E63)

E63a: 4-[4-(1-Naphthoyl)piperazin-1-yl]phenol

To a stirring mixture of 4-(1-piperazinyl)phenol (5.54 g) andtriethylamine (10.83 ml) in dichloromethane (140 ml) was added dropwise,1-naphthalenecarbonyl chloride (9.83 ml). The resulting reaction mixturewas stirred under a nitrogen atmosphere for 3 h. The mixture waspartitioned between dichloromethane and water and the organic phase waswashed with saturated brine, dried (MgSO₄) and evaporated to dryness.The residue was suspended in 6:4 tetrahydrofuran-methanol (370 ml) andtreated with a saturated solution of potassium carbonate in methanol (45ml). The mixture was stirred at room temperature under a nitrogenatmosphere for 20 h. The solvent was evaporated and the residue waspartitioned between dichloromethane and water. The organic phase waswashed with saturated brine, dried (MgSO₄) and evaporated to give an oil(15.5 g), part of which (14.5 g) was purified by chromatography on asilica SPE bond elut cartridge eluting with 10%-80% ethylacetate-cyclohexane gradient to give the title compound (8.9 g). LCMSRT=2.97 min.

E63b: 1-[4-(3-Chloropropoxy)phenyl]-4-(1-naphthoyl)piperazine

Was prepared from 4-[4-(1-naphthoyl)piperazin-1-yl]phenol (E63a) and1-bromo-3-chloropropane using the same method described in Description 9LCMS RT=3.59 min

E63c: 1-(1-Naphthoyl)-4-[4-(3-piperidin-1-ylpropoxy)phenyl]piperazinetrifluoroacetate

1-[4-(3-Chloropropoxy)phenyl]-4-(1-naphthoyl)piperazine (E63b) (27 mg)piperidine (0.033 ml), potassium carbonate (46 mg), potassium iodide (56mg) in 2-butanone (2 ml) was heated to reflux for 36 h. The solvent wasremoved at room temperature by a stream of nitrogen gas. The residue wasdissolved in water and dichloromethane. The organic layer was separated,concentrated and purified by mass directed preparative HPLC to give thetitle compound (23 mg). LCMS RT=2.15 min, ES+ve m/z 458 (M+H)⁺.

EXAMPLES 64-75

Examples 64-75 were prepared in an array format using the same methoddescribed in Example 63c from1-[4-(3-chloropropoxy)phenyl]-4-(1-naphthoyl)piperazine (0.067 mmol),the appropriate secondary amine (5.0 eq), potassium carbonate (5.0 eq),and potassium iodide (5.0 eq) in 2-butanone (2 ml). The products werepurified by mass directed auto-preparative HPLC to provide the compoundsas TFA salts.

Mass Ion Example Structure RT (min) (M + H)⁺ 64

2.76 500 65

2.63 472 66

2.55 476 67

2.27 486 68

2.66 472 69

2.58 458 70

2.71 485.73 71

2.22 472 72

2.22 472 73

2.26 514 74

2.35 500 75

2.24 486

EXAMPLE 765-Fluoro-1-methyl-3-[(4-{4-[3-(2-methylpiperidin-1-yl)propoxy]phenyl}piperazin-1-yl)carbonyl]-1H-indole(E76)

E76a: 1,1-Dimethylethyl4-(4-{[3-(2-methyl-1-piperidinyl)propyl]oxy}phenyl)-1-piperazinecarboxylate

1,1-Dimethylethyl4-{4-[(3-chloropropyl)oxy]phenyl}-1-piperazinecarboxylate (D9) (1.6 g),was dissolved in 2-butanone (10 ml). Potassium carbonate (1.38 g) and acatalytic amount of potassium iodide were added, followed by2-methylpiperidine (0.99 g). The mixture was heated at reflux for 72 hunder nitrogen. The reaction mixture was diluted with water andextracted with dichloromethane. The organic phases were separated usinga hydrophobic frit, combined and evaporated in vacuo. The residue waspurified on a 100 g silica SPE bond elut cartridge, eluting with agradient of 0% to 20% [0.880 ammonia-methanol (1:9)]-dichloromethanemixtures, to give the title compound (1.66 g). LCMS RT=2.48 min.

E76b: 1-(4-{[3-(2-Methyl-1-piperidinyl)propyl]oxy}phenyl)piperazine

1,1-Dimethylethyl 4-(4-{[3-(2-methyl-1-piperidinyl)propyl]oxy}phenyl)-1-piperazinecarboxylate (E76a) (1.66 g) was dissolvedin dry dichloromethane (25 ml) and stirred under nitrogen. 50%Trifluoroacetic acid in dichloromethane (5 ml) was added, and themixture was stirred at room temperature for 4 h. Saturated sodiumbicarbonate solution was then added and the mixture was extracted withdichloromethane. The organic phase was separated using a hydrophobicfrit, and evaporated in vacuo, however, most of the product was in theaqueous phase. The product was removed from the aqueous phase using anOASIS cartridge, washing with water and eluting with methanol, andfurther purified using an aminopropyl bond elut cartridge, eluting withdichloromethane and then SCX cartridge, eluting with 50% [0.880ammonia-methanol (1:9)]-dichloromethane to give the title compound (0.94g). LCMS RT=1.01 min, ES+ve m/z=318 (M+H)⁺

E76c:5-Fluoro-1-methyl-3-[(4-{4-[3-(2-methylpiperidin-1-yl)propoxy]phenyl}piperazin-1-yl)carbonyl]-1H-indole

A solution of 5-fluoro-1-methyl-1H-indole-3-carboxylic acid (19.3 mg)and O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (TBTU) (56 mg) in DMF (1 ml) and diisopropylethylamine(0.035 ml) was stirred for 10 min before1-{4-[3-(2-methylpiperidin-1-yl)propoxy]phenyl}piperazine (E76b) (21.3mg) in DMF (0.5 ml) was added. The mixture was stirred for 18 h and thenconcentrated under reduced pressure. The residue was purified by SPE ionexchange chromatography on an SCX-2 cartridge (1 g). The cartridge waswashed with methanol (3 ml) and the product eluted with 2M ammonia inmethanol (2.5 ml), to give the title compound (15 mg) LCMS RT=2.42 min,ES+ve m/z 493 (M+H)⁺.

EXAMPLES 77-224

Examples 77 to 224 were prepared in an array format in vials using asolution of the appropriate carboxylic acid (0.1 mmol) in DMF (0.5 ml)and a solution of O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (TBTU) (0.15 mmol) in DMF (0.5 ml) anddiisopropylethylamine (0.2 mmol). Each vial was shaken manually andstood for 10 min, before a solution of the appropriate piperazine(selected from D18-D23 or D46 in the case of Example 99) (0.067 mmol) inDMF (0.5 ml) was added to each reaction mixture. The vials were left tostand overnight for approximately 18 h at room temperature. Eachsolution was then added to the top of a preconditioned SCX-2 SPEcartridge (1 g). The cartridge was washed with methanol (3 ml) and theproduct eluted with 2M ammonia in methanol (2.5 ml), into pre-weighedvials. The solutions were evaporated to dryness on the genevac toprovide the products (Examples 77-222). Examples 151, 154, 162-171 and206-222 were further purified by mass directed auto-preparative HPLC toprovide the products as trifluoroacetate salts.

Mass ion Example Structure RT (min) (M + H)⁺ 77

2.36 438 78

2.52 464 79

2.55 466 80

2.44 452 81

2.74 484 82

2.52 436 83

2.74 480 84

2.58 476 85

2.50 442 444 86

2.39 444 87

2.50 434 88

2.36 485 89

2.58 480 90

2.34 480 91

2.66 480 92

2.23 456 93

2.76 464 94

2.24 424 95

2.16 468 96

1.87 463 97

1.96 463 98

1.85 467 99

2.11 461 100

2.37 484 101

2.11 485 102

2.05 473 475 103

2.07 460 462 104

2.07 478 105

2.18 476 478 106

2.13 466 107

2.05 440 108

2.20 450 109

2.31 464 110

2.31 464 111

2.29 464 112

2.22 462 113

2.07 436 114

2.07 436 115

2.12 476 478 116

2.13 448 117

2.26 480 118

2.29 478 119

2.15 485 120

2.52 472 121

2.52 452 122

2.63 475 123

2.53 464 124

2.53 480 125

2.60 464 126

2.47 468 127

2.59 464 128

2.61 537 129

2.37 475 130

2.58 534 131

2.66 518 520 132

2.54 494 133

2.76 504 134

2.60 478 135

2.60 517 136

2.65 588 137

2.83 579 138

2.60 476 139

2.63 536 140

2.69 542 544 141

2.62 528 530 142

2.68 589 143

2.61 521 144

2.58 478 145

2.70 492 146

2.81 506 147

2.77 522 148

2.77 506 149

2.59 464 150

2.57 464 151

2.27 486 152

2.60 478 153

2.63 494 154

2.36 466 155

2.36 466 156

2.65 478 157

2.54 464 158

2.40 450 159

2.42 493 160

2.42 561 161

2.51 500 502 162

2.66 492 163

2.60 528 530 164

2.54 522 165

2.51 462 166

2.76 565 167

2.55 504 168

2.51 464 169

2.67 490 170

2.45 480 171

2.57 504 506 172

2.63 478 173

2.65 494 174

2.69 478 175

2.56 482 176

2.49 500 502 177

2.66 478 178

2.55 514 516 179

2.47 448 180

2.72 551 181

2.52 560 182

2.47 489 183

2.54 490 184

2.47 450 185

2.60 476 186

2.39 466 187

2.53 491 188

2.63 478 189

2.64 494 190

2.68 478 191

2.58 482 192

2.55 464 193

2.44 450 194

2.47 500 502 195

2.66 478 196

2.44 508 197

2.44 448 198

2.71 551 199

2.52 560 200

2.46 489 201

2.50 490 202

2.46 450 203

2.62 476 204

2.39 466 205

2.52 490 492 206

2.40 508 207

2.37 496 208

2.35 478 209

2.27 464 210

2.37 504 506 211

2.26 514 516 212

2.34 528 530 213

2.00 514 214

2.28 522 215

2.26 462 216

2.57 574 217

2.30 503 218

2.30 504 219

2.29 464 220

2.31 504 506 221

2.09 524 222

2.26 520 223

2.77 506 224

2.49 492

EXAMPLE 2251-[3-Chloro-4-(3-piperidin-1-ylpropoxy)phenyl]-4-(1-naphthoyl)piperazineformate (E225)

E225a: tert-Butyl 4-(1-naphthoyl)piperazine-1-carboxylate

1-Naphthoyl chloride (2.15 ml) was added to a solution of tert-butylpiperazine-1-carboxylate (3.28 g) and diisopropylethylamine (3.44 ml) indichloromethane (100 ml) at 0° C. After 2 h stirring the mixture waspartitioned between dichloromethane and 2M hydrochloric acid. Theorganic phase was washed with sat. aq. sodium bicarbonate solution,dried (MgSO₄) and evaporated to dryness to give the title compound (4.9g) LCMS RT=3.16 min.

E225b: 1-(1-Naphthoyl)piperazine

tert-Butyl 4-(1-naphthoyl)piperazine-1-carboxylate (E225a) (4.2 g) wasdissolved in dichloromethane (80 ml) and treated with trifluoroaceticacid (10 ml) for 4.5 h at 20° C. The solvent was removed under reducedpressure and the residue was partitioned between dichloromethane and 2Msodium hydroxide. The organic phase was dried (MgSO₄) and evaporated todryness to give the title compound (3.19 g) LCMS RT=1.50 min.

E225c: 2-Chloro-4-[4-(1-naphthoyl)piperazin-1-yl]phenol

A mixture of 1-(1-naphthoyl)piperazine (E225b) (143.7 mg),4-bromo-2-chlorophenol (207 mg), tris(dibenzylideneacetone) dipalladium(4.75 mg), 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (4.91mg) was dissolved in tetrahydrofuran (3 ml) and then treated at 0° C.with 1M solution of lithium bis(trimethylsilyl)amide (1.1 ml) undernitrogen. The mixture was heated to 70° C. for 18 h and then partitionedbetween water and dichloromethane. The organic phase was separated usinghydrophobic frit, and purified on a silica SPE bond elut cartridgeeluting with aq. ammonia-methanol-dichloromethane (1:2:98) to give thetitle compound (81 mg) LCMS RT=3.16 min.

E225d:1-[3-Chloro-4-(3-piperidin-1-ylpropoxy)phenyl]-4-(1-naphthoyl)piperazineformate

2-Chloro-4-[4-(1-naphthoyl)piperazin-1-yl]phenol (E225c) (37 mg),caesium carbonate (81 mg), sodium iodide (2.3 mg),1-(3-chloropropyl)piperidine (22 mg) in DMF (2.5 ml) were heated in amicrowave oven at 160° C. for 10 min and at 170° C. for 20 min. Thereaction mixture was poured into water and extracted with ethyl acetate.The organic phase was washed with brine, dried (MgSO₄), and purified bymass directed auto-preparative HPLC to give the title compound (30 mg)LCMS RT=2.60 min, ES+ve m/z 492 and 494.

EXAMPLE 2261-(2-Bromo-4-{[3-(1-piperidinyl)propyl]oxy}phenyl)-4-(1-naphthalenylcarbonyl)piperazine(E226)

E226a: 4-(4-Acetylpiperazin-1-yl)-3-bromophenyl acetate

4-(4-Acetylpiperazin-1-yl)phenol (38.5 g) in dichloromethane (875 ml)was treated with triethylamine (35 ml) and the solution was cooled inice. Acetyl chloride (15.05 ml) in dichloromethane (87 ml) was addeddropwise with stirring, keeping the temperature between 18 and 20°.After 30 min, the solution was washed with water, dried and evaporatedto give 4-(4-acetylpiperazin-1-yl)phenyl acetate (44.2 g). A portion ofthis (31.4 g) was dissolved in acetic acid (720 ml) and sodium acetate(19.7 g) was added. The solution was cooled to 15°, and bromine (6.2 ml)in acetic acid (72 ml) was added dropwise with stirring over 15 min,keeping the temp. at 15° C. After 30 min, aqueous sodium metabisulphitesolution (4.6 g in 60 ml water) was added and the mixture wasconcentrated by evaporation to ca. 200 ml. Dichloromethane (500 ml) wasadded, followed by sodium bicarbonate solution until the pH of theaqueous layer was 5. The dichloromethane layer was diluted (1 L) andseparated, washed with an equal volume of water, dried, evaporated andpurified by chromatography on Biotage (800 g cartridge) eluting withethyl acetate-hexane (3:1) to give the title compound. (34.8 g) mp 75°C.

E226b: 4-(4-Acetylpiperazin-1-yl)-3-bromophenol

A solution of 4-(4-acetylpiperazin-1-yl)-3-bromophenyl acetate (E226a)(29.5 g) in methanol (300 ml) was cooled in an ice bath to 15° C. andtreated dropwise with 2N NaOH aqueous solution (87 ml). After 30 min,the solution was poured into ice-water (1.7 L) and the mixture acidifiedto pH 6. The white precipitate was collected by filtration and washedwith water (0.5 L). Drying under vacuum gave the title compound (22.8g), mp 212-4° C.

E226c: 1-(2-Bromo-4-{[3-(1-piperidinyl)propyl]oxy}phenyl)piperazine

A mixture of 4-(4-acetyl-1-piperazinyl)-3-bromophenol (E226b) (1 g) inDMF (10 ml) and chloropropyl piperidine hydrochloride (0.72 g), Cs₂CO₃(2.99 g), and NaI (75 mg) was heated at 80° C. for 24 h. The mixture wascooled to room temperature and quenched with water (10 ml), thenextracted with ethyl acetate and evaporated. The residue was treatedwith 5 ml of conc. HCl and 5 ml of water and heated to reflux. Thereaction mixture was cooled to 20° C. and diluted with water (10 ml),basified with solid potassium carbonate and extracted with DCM. Theresidue was purified by chromatography on biotage (40 g cartridge)eluting with DCM-EtOH—NH₃ (45:5:1) to give the title compound (0.86 g)LCMS RT=1.68 min, ES+ve m/z 382, 384 (M+H)⁺.

E226d:1-(2-Bromo-4-{[3-(1-piperidinyl)propyl]oxy}phenyl)-4-(1-naphthalenylcarbonyl)piperazine

A solution of1-(2-bromo-4-{[3-(1-piperidinyl)propyl]oxy}phenyl)piperazine (E226c)(0.86 g) in anhydrous DCM (10 ml) and triethylamine (0.34 ml) was cooledto 0° C. and naphthoyl chloride (0.37 ml) was added. The mixture wasstirred under nitrogen for 48 h, evaporated to dryness and partitionedbetween saturated sodium bicarbonate solution and DCM. The organic phasewas separated, concentrated and the residue was purified bychromatography on biotage (40 g cartridge) eluting with DCM-MeOH-aqueousNH₃ (200:8:1) to afford the title compound (1.2 g). LCMS RT=2.71 min,ES+ve m/z 536, 538 (M+H)⁺.

EXAMPLE 2271-(2-Methyl-4-{[3-(1-piperidinyl)propyl]oxy}phenyl)-4-(1-naphthalenylcarbonyl)piperazine(E227)

A solution of1-(2-bromo-4-{[3-(1-piperidinyl)propyl]oxy}phenyl)-4-(1-naphthalenylcarbonyl)piperazine(E226) (50 mg), tetrakis(triphenylphosphine) palladium (0) (10 mg),potassium carbonate (38 mg) and trimethylboroxine (23 mg) in of DMF (1ml) was heated at 150° C. in a microwave oven for 10 min, cooled,evaporated to dryness and purified by chromatography on a biotagecartridge eluting with DCM-MeOH— aqueous NH₃ (200:8:1) to afford thetitle compound (21 mg). LCMS RT=2.63 min, 472 (M+H)⁺.

EXAMPLE 2281-{[5-Methyl-2-(methyloxy)phenyl]methyl}-4-(4-{[3-(1-piperidinyl)propyl]oxy}phenyl)piperazineformate (E228)

A solution of 5-methyl-2-(methyloxy)benzaldehyde (40 mg) and1-(4-{[3-(1-piperidinyl)propyl]oxy}phenyl)piperazine [D11] (40 mg) indichloromethane (2 ml) was treated with acetic acid (7.9 μl) and sodiumtriacetoxyborohydride (56 mg). The resulting suspension was stirred at22° C. for 24 h. The reaction mixture was concentrated and purified bymass directed auto preparative HPLC to give the title compound (4.8 mg).LCMS RT=1.99 min, 438 (MH⁺).

EXAMPLE 2298-{4-[(3-{[3-(1-Piperidinyl)propyl]oxy}phenyl)methyl]-1-piperazinyl}quinolinetrifluoroacetate (E229)

E229a: 1,1-Dimethylethyl 4-(8-quinolinyl)-1-piperazinecarboxylate

A solution of 8-bromoquinoline (28.6 mg) in dry THF (1 mL) was treatedwith 1,1-dimethylethyl 1-piperazinecarboxylate (30.7 mg),tris(dibenzylidineacetone) dipalladium (0) (1.5 mg) and2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (1.6 mg). Thereaction mixture was treated with lithium bis(trimethylsilyl)amide (1Min THF, 0.27 mL) and then heated at 75° C. for 4 h. The reaction mixturewas cooled to room temperature and concentrated in vacuo. The residuewas purified by chromatography (silica SPE bond elut cartridge), elutingwith a gradient between cyclohexane and EtOAc to give the title compound(29 mg). LCMS RT=2.86 min.

E229b: 8-(1-piperazinyl)quinoline

A solution of 1,1-dimethylethyl 4-(8-quinolinyl)-1-piperazinecarboxylate(E229c) (2.5 g) in DCM (60 mL) was treated with TFA (20 mL) and stirredat room temperature for 4 h prior to pouring into DCM and washing withsaturated NaHCO_(3 (Aq)). The organic phase was washed with water, dried(MgSO₄) and concentrated in vacuo. The residue was purified bychromatography (silica SPE cartridge), eluting with gradient between DCMand 100:10:1 DCM-MeOH— aqueous NH₃) to give the title compound (643 mg).LCMS RT=0.68 min.

E229c: 3-{[4-(8-Quinolinyl)-1-piperazinyl]methyl}phenol

A solution of 8-(1-piperazinyl)quinoline (E229b) (126 mg) in dry DCM (2mL) was treated with AcOH (500 μL). A solution of 3-hydroxybenzaldehyde(88 mg) in dry DCM (3 mL) was added followed by sodium borohydride (191mg). The reaction mixture was stirred for 16 h prior to the addition ofwater. The aqueous phase was neutralised with 2N NaOH. The organic phasewas extracted twice with DCM and the combined organic phase concentratedin vacuo. The residue was purified by chromatography (silica SPE)eluting with a gradient between DCM and 100:10:1 DCM-MeOH-aqueous NH₃)to give the title compound (133 mg). LCMS RT=1.96 min.

E229d:8-{4-[(3-{[3-(1-Piperidinyl)propyl]oxy}phenyl)methyl]-1-piperazinyl}quinolinetrifluoroacetate

A solution of 1-(3-chloropropyl)piperidine hydrochloride (46 mg) in dryDMF was treated with a solution of3-{[4-(8-quinolinyl)-1-piperazinyl]methyl}phenol (E229c) (43 mg). Theresultant solution was treated with sodium hydride (60% oil dispersion,11 mg) and stirred at room temperature for 16 h. The reaction mixturewas quenched with water (1 drop) and partitioned between water and DCM.The organic phase was concentrated in vacuo. The residue was purified bymass directed auto-preparative HPLC to give the title compound (5.7 mg).LCMS RT=1.83 min, ES+ve m/z 445 (MH)⁺

EXAMPLES 230-236

Examples 230-236 were prepared in an analogous manner to that describedfor E229d from known starting materials and those indicated in the tablebelow:

Starting RT Mass ion Example Structure Materials (min) (M + H)⁺ 230

D30 1.86 458 231

D30 1.78 444 232

D30 1.82 458 233

D28 3.59 457 234

D29 2.18 457 235

D32 2.14 457 236

D31 1.67 & 1.89 459 & 459

EXAMPLE 2378-{4-[2-(4-{[3-(1-Piperidinyl)propyl]oxy}phenyl)ethyl]-1-piperazinyl}quinolinetrifluoroacetate (E237)

E237a:8-[4-(2-{4-[(Phenylmethyl)oxy]phenyl}ethyl)-1-piperazinyl]quinoline

A solution of 8-(1-piperazinyl)quinoline (E229b) (126 mg) in dry DMF (2mL) was treated with diisopropylethylamine (176 μL) followed by asolution of 1-(2-bromoethyl)-4-[(phenylmethyl)oxy]benzene (277 mg) indry DMF (1 mL). The resultant reaction mixture was stirred undernitrogen for 18 h prior to quenching with water. The reaction mixturewas partitioned between water and DCM and the organic phase dried(MgSO₄) and concentrated in vacuo. The residue was purified bychromatography on silica SPE, eluting with a gradient between DCM and100:10:1 DCM-MeOH-aqueous NH₃ to give the title compound (51 mg).

LCMS RT=2.54 min.

E237b: 4-{2-[4-(8-Quinolinyl)-1-piperazinyl]ethyl}phenol

A solution of8-[4-(2-{4-[(phenylmethyl)oxy]phenyl}ethyl)-1-piperazinyl]quinoline(E237a) (107 mg) in dry DCM (5 mL) was cooled to −20° C. and treatedwith a solution of boron tribromide (1M in DCM, 2504). The reactionmixture was stirred at −20° C. for 30 min and at room temp. for 12 h.The reaction mixture was concentrated in vacuo. The residue was purifiedby chromatography on silica SPE eluting with a gradient between DCM and100:10:1 DCM-MeOH-aqueous NH₃) to give the title compound (51 mg). LCMSRT=1.73 min.

E237c:8-{4-[2-(4-{[3-(1-Piperidinyl)propyl]oxy}phenyl)ethyl]-1-piperazinyl}quinolinetrifluoroacetate

Was prepared using the method described in E228d LCMS RT=2.32 min, ES+vem/z 460 (M+H)^(±).

EXAMPLES 238-244

Examples 238-244 were prepared in an analogous manner to that describedfor E229d from known starting materials and those indicated in the tablebelow:

Starting RT Mass ion Example Structure Materials (min) (M + H)⁺ 238

 E237b 2.19 474 239

D38 1.68 474 240

D39 1.73 486 241

D39 1.75 473 242

D40 1.82 459 243

D41 3.01 459 244

D42 2.15 408

EXAMPLE 2451-Diphenylacetyl-4-[4-(3-piperidin-1-ylpropoxy)phenyl]piperazine (E245)

A solution of diphenylacetic acid (11 mg, 50 mmol) in DMF (1 ml) wastreated with a solution of1-[4-(3-piperidin-1-ylpropoxy)phenyl]piperazine (D11) (15 mg) in DMF (1ml), followed by triethylamine (20 μl) and HBTU (19 mg). The mixture wasshaken for 5 min then left to stand at room temperature overnight.Polystyryl-trisamine (100 mmol) and polystyryl-isocyanate (50 μmol) wereadded and the mixture shaken for a further 20 h. The mixture was thenfiltered and the filtrate loaded onto a solid phase cation exchange(SCX) cartridge.

After washing with 80% MeOH-DCM, the product was eluted with a solutionof NH₃ in MeOH (0.5 M). The eluted fraction was concentrated to drynessunder vacuum giving the title compound (17.5 mg). LCMS RT=3.36 min,ES+ve m/z 498 (M+H)⁺.

EXAMPLE 2461-(Naphthalen-1-ylsulfonyl)-4-[4-(3-piperidin-1-ylpropoxy)phenyl]piperazine(E246)

A solution of 1-[4-(3-piperidin-1-ylpropoxy)phenyl]piperazine (D11) (30mg) in DCM (3 ml) was treated with a solution of naphthalene-1-sulfonylchloride (27 mg) in DCM (1 ml). Polystyryl-methylmorpholine (200 mmol)was added and the mixture shaken at room temperature for 24 h. Themixture was loaded onto a SCX cartridge and after washing with 50%MeOH-DCM, the crude product was eluted with a solution of NH₃ in MeOH(0.5 M). The eluted fraction was concentrated to dryness under vacuumand purified by flash silica chromatography, eluting with 5% MeOH-DCM,to give the title compound (22 mg). LCMS RT=3.30 min, ES+ve m/z 394(M+H)⁺.

EXAMPLE 2471-(9H-Xanthen-9-ylcarbonyl)-4-[4-(3-piperidin-1-ylpropoxy)phenyl]piperazine(E247)

Polystyryl-carbodiimide (450 mmol) was treated with a solution of9H-xanthene-9-carboxylic acid (34 mg) in DMF (2 ml) and shaken for 5 minthen treated with a solution of1-[4-(3-piperidin-1-ylpropoxy)phenyl]piperazine (D11) (30 mg) in DMF (1ml) and shaken at room temperature for 20 h. Polystyryl-isocyanate (100mmol) was added and the mixture shaken for a further 24 h. The mixturewas then filtered and the filtrate loaded onto a SCX cartridge. Afterwashing with 80% MeOH-DCM, the crude product was eluted with a solutionof NH₃ in MeOH (0.5 M). The eluted fraction was concentrated to drynessunder vacuum and purified by flash silica chromatography, eluting with5-10% MeOH-DCM gradient, to give the title compound (5.7 mg). LCMSRT=3.16 min, ES+ve m/z 512 [M+H]⁺.

EXAMPLES 248-251

Examples 248-251 were prepared according to the procedure for Example247.

RT Mass ion Example Structure (min) (M + H)⁺ 248

3.08 496 249

1.98 459 250

2.24 501 251

2.14 465

EXAMPLE 2521-(4-Carboxy-1-naphthoyl)-4-[4-(3-piperidin-1-ylpropoxy)phenyl]piperazinedi(trifluoroacetate) (E252)

A solution of 1,4-dinaphthoic acid (50 mg) in DMF (2 ml) was treatedwith a solution of 1-[4-(3-piperidin-1-ylpropoxy)phenyl]piperazine (D11)(70 mg) in DMF (1.5 ml) followed by HBTU (88 mg). The mixture was shakenfor 5 min then left to stand at room temperature overnight. Water (100μl) was added, then the mixture was concentrated to dryness under vacuumand purified using reverse phase HPLC, affording the title compound (80mg).

LCMS RT=2.36 min. ES+ve m/z 502 [M+H]⁺.

EXAMPLE 253

1-[4-(Methoxycarbonylmethoxy)naphth-1-oyl]-4-[4-(3-piperidin-1-ylpropoxy)phenyl]piperazine(E253)

E253a: 4-(Methoxycarbonylmethoxy)naphthalene-1-carboxylic acid

To a solution of methyl (4-formylnaphthalen-1-yloxy)acetate (J. Med.Chem. 2002, 45, 5755) (2.35 g) in t-BuOH (10 ml), acetone (10 ml), andH₂O (5 ml) at 0° C. were added solid NaClO₂ (1.30 g) and NaH₂PO₄.H₂O(1.99 g) and the mixture was stirred at room temperature under nitrogenovernight. Further NaClO₂ (1.73 g) and Na₃PO₄ (2.66 g) dissolved in H₂O(3 ml) were added and the reaction continued for 24 h. The mixture wasthen concentrated under vacuum and treated with H₂O. The resultantprecipitate was collected by filtration, washed with H₂O, and driedunder vacuum to give the title compound (2.2 g). ¹H-NMR δ (DMSO-d₆, 400MHz) 12.74 (br. s, 1H), 8.97 (d, 1H), 8.27 (d, 1H), 8.13 (d, 1H), 7.63(m, 1H), 7.58 (m, 1H), 6.95 (d, 1H), 5.07 (s, 2H), 3.70 (s, 3H).

E253b:1-[4-(Methoxycarbonylmethoxy)naphth-1-oyl]-4-[4-(3-piperidin-1-ylpropoxy)phenyl]piperazine

The title compound was prepared from 4-(methoxycarbonylmethoxy)naphthalene-1-carboxylic acid (E253a) (50 mg) and1-[4-(3-piperidin-1-ylpropoxy)phenyl]piperazine (D11) (58 mg) accordingto the procedure for Example 252 (76 mg). LCMS RT=2.79 min, ES+ve m/z545 [M+H]⁺.

EXAMPLE 2541-[4-(Carboxymethoxy)naphth-1-oyl]-4-[4[(3-piperidin-1-ylpropoxy)phenyl]piperazine(E254)

A stirred solution of1-[4-(methoxycarbonylmethoxy)naphth-1-oyl]-4-[4-(3-piperidin-1-ylpropoxy)phenyl]piperazine(E253b) (38 mg) in THF (2 ml) was treated with a solution of KOH (6 mg)in H₂O (1 ml). After 1.5 h the mixture was treated with a solution of 2MHCl in Et₂O (50 μl) and concentrated to dryness under vacuum. Theresidue was treated with EtOH, then filtered and the filtrateconcentrated to dryness under vacuum to give the title compound (29 mg).LCMS RT=2.42 min, ES+ve m/z 532 [M+H]⁺.

EXAMPLE 2551-[(4-Fluorophenyl)carbonyl]-4-(4-{[1-(1-methylethyl)-4-piperidinyl]oxy}phenyl)piperazine(E255)

Step 1: 4-{4[(4-Fluorophenyl)carbonyl]-1-piperazinyl}phenol

4-Fluorobenzoylchloride (1.59 ml, 18.5 mmol) in dichloromethane (15 ml)was added to an ice cooled mixture of 4-(1-piperazinyl)phenol (3 g, 16.8ml) and triethylamine (2.8 ml, 20.2 mmol). The resulting mixture wasstirred at room temperature for 18 hours. The solvent was removed byevaporation and the residue dissolved in methanol (30 ml). This wastreated with potassium carbonate (5 g) for 30 minutes and filtered. Thefiltrate was evaporated and dissolved in ethyl acetate. This solutionwas washed with saturated sodium hydrogen carbonate solution, dried(sodium sulphate) and evaporated to give a pink solid (2.58 g, 51%) MS(ES+) m/e 301 [M+H]⁺.

Step 2: 1,1-Dimethylethyl4-[(4-{4-[(4-fluorophenyl)carbonyl]-1-piperazinyl}phenyl)oxy]-1-piperidinecarboxylate

Di-tert-butyl azodicarboxylate (2.4 g, 10.3 mmol) was added to a mixtureof 4-{4-[(4-fluorophenyl)carbonyl]-1-piperazinyl}phenol (2.57 g, 8.6mmol), triphenyl phospine (2.7 g, 10.3 mmol) and 1,1-dimethylethyl4-hydroxy-1-piperidinecarboxylate (2 g, 10.3 mmol) in tetrahydrofuran(30 ml). The mixture was stirred at room temperature for 18 hours. Thereaction was diluted with ethyl acetate and washed with 2 molar sodiumhydroxide solution. The organic portion was dried (sodium sulphate) andevaporated. The residue was purified on a silica gel column eluting witha mixture of hexane:ethyl acetate (1:1) to afford the title compound(2.75 g, 67%) MS (ES+) m/e 484 [M+H]⁺.

Step 3:1-[(4-Fluorophenyl)carbonyl]-4-[4-(4-piperidinyloxy)phenyl]piperazine

A solution of 1,1-dimethylethyl4-[(4-{4-[(4-fluorophenyl)carbonyl]-1-piperazinyl}phenyl)oxy]-1-piperidinecarboxylate(2.75 g, 5.7 mmol) in trifluoroacetic acid (10 ml) was stirred at roomtemperature for 30 minutes. The solvent was removed by evaporation andthe residue purified on SCX ion exchange resin eluting with methanol andthen a mixture of 0.88 ammonia:methanol (1:9) to afford the titlecompound (2.1 g, 95%) MS (ES+) m/e 384 [M+H]⁺.

Step 4:1-[(4-Fluorophenyl)carbonyl]-4-(4-{[1-(1-methylethyl)-4-piperidinyl]oxy}phenyl)piperazine

Sodium triacetoxyborohydride (360 mg, 1.72 mmol) was added to a solutionof 1-[(4-fluorophenyl)carbonyl]-4-[4-(4-piperidinyloxy)phenyl]piperazine(330 mg, 0.86 mmol) and acetone (126 μl, 1.72 mmol) in dichloromethane(5 ml). After stirring at room temperature for 18 hours, with 2 molarsodium hydroxide solution was added and the mixture extracted with ethylacetate. The extracts were dried (sodium sulphate) and evaporated. Theresidue was purified on a silica gel column eluting with a mixture ofmethanol: 0.88 ammonia:methanol:dichloromethane (0.5:4.5:95) to affordthe title compound (191 mg, 52%)

MS (ES+) m/e 426 [M+H]⁺.

EXAMPLES 256-259

Examples 256-259 were prepared in the same manner as Example 255 usingthe appropriate ketone or aldehyde as indicated in the table:

MS (ES+) m/e Compound Ketone/Aldehyde [M + H]⁺.1-(4-{[1-(Cyclopropylmethyl)-4- cyclopropane 475piperidinyl]oxy}phenyl)-4-[(4- carbaldehydefluorophenyl)carbonyl]piperazine (E256)1-[(4-Fluorophenyl)carbonyl]-4-(4-{[1-(2- 2-methylpropanal 440methylpropyl)-4-piperidinyl]oxy}phenyl)piperazine (E257)1-{4-[(1-Cyclopentyl-4-piperidinyl)oxy]phenyl}-4- cyclopentanone 452[(4-fluorophenyl)carbonyl]piperazine (E258)1-{4-[(1-Cyclobutyl-4-piperidinyl)oxy]phenyl}-4- cyclobutanone 438[(4-fluorophenyl)carbonyl]piperazine (E259)

EXAMPLE 2601-{4-[(1-Cyclopropyl-4-piperidinyl)oxy]phenyl}-4-[(4-fluorophenyl)carbonyl]piperazine(E260)

{[1-(ethyloxy)cyclopropyl]oxy}(trimethyl)silane 524 μl, 2.6 mmol) wasadded to a stirring mixture of the product of Example 255, step 3(1-[(4-fluorophenyl)carbonyl]-4-[4-(4-piperidinyloxy)phenyl]piperazine)(250 mg, 0.65 mmol) and polymer bound cyanoborohydride (650 mg of 4mmol/g resin) in methanol (10 ml) and acetic acid (250 μl). This mixturewas heated at 50° C. for 18 hours. The mixture was filtered and thefiltrate evaporated. The residue was purified on a silica cartridgeeluting with a mixture of: 0.88 ammonia:methanol:dichloromethane(0.5:4.5:95) to afford the title compound (155 mg, 56%)

MS (ES+) m/e 424 [M+H]⁺.

EXAMPLES 261-262

Examples 261-262 may be prepared in an analogous manner to thatdescribed in Example 255, step 4 from pentan-3-one and the product ofExample 255, step 3.

Compound Structure 1-(4-{4-[1-(1-Ethyl-propyl)-piperidin-4-yloxy]-phenyl}-piperazin-1-yl)-1-(4-fluoro- phenyl)-methanone (E261)

1-{4-[4-(1-sec-Butyl-piperidin-4-yloxy)-phenyl]-piperazin-1-yl}-1-(4-fluoro- phenyl)-methanone (E262)

EXAMPLE 2631-(4-{[1-(1-Methylethyl)-4-piperidinyl]oxy}phenyl)-4-(tetrahydro-2H-pyran-4-ylcarbonyl)piperazine(E263)

Step 1: 1,1-Dimethylethyl 4-[(4-iodophenyl)oxy]-1-piperidinecarboxylate

Di-tert-butyl azodicarboxylate (5.9 g, 25.8 mmol) was added to a mixtureof 4-iodophenol (4.72 g, 21.5 mmol), triphenyl phospine (6.8 g, 25.8mmol) and 1,1-dimethylethyl 4-hydroxy-1-piperidinecarboxylate (5.18 g,25.8 mmol) in tetrahydrofuran (100 ml). The mixture was stirred at roomtemperature for 18 hours. The reaction was diluted with ethyl acetateand washed with 2 molar sodium hydroxide solution. The organic portionwas dried (sodium sulphate) and evaporated. The residue was purified ona silica column eluting with 9-1 hexane-ethyl acetate to afford thetitle compound (5.5 g, 64%) MS (ES+) m/e 304 [M+H]⁺-BOC.

Step 2: 4-[(4-Iodophenyl)oxy]piperidine

Product of Step 1 (1,1-dimethylethyl4-[(4-iodophenyl)oxy]-1-piperidinecarboxylate) (5.5 g, 13.6 mmol) intrifluoroacetic acid (10 ml) was stirred at room temperature for 30minutes. The solvent was removed by evaporation and the residue basifiedusing 2M sodium hydroxide solution. This was extracted intodichloromethane, the extracts were dried (sodium sulphate) andevaporated to afford the title compound (3.4 g, 82%) MS (ES+) m/e 304[M+H]⁺.

Step 3: 4-[(4-Iodophenyl)oxy]-1-(1-methylethyl)piperidine

Sodium triacetoxyborohydride (4.75 mg, 22.4 mmol) was added to asolution of the product of Step 2 (4-[(4-iodophenyl)oxy]piperidine) (3.4g, 11.2 mmol) and acetone (1.65 ml, 22.4 mmol) in dichloromethane (70ml). After stirring at room temperature for 18 hours, 2 molar sodiumhydroxide solution was added and the mixture extracted with ethylacetate. The extracts were dried (sodium sulphate) and evaporated toafford the title compound (3.63 mg, 94%) MS (ES+) m/e 346 [M+H]⁺.

Step 4: 1,1-Dimethylethyl4-(4-{[1-(1-methylethyl)-4-piperidinyl]oxy}phenyl)-1-piperazinecarboxylate

A mixture of palladium acetate (32 mg, 5 mol %) and2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (135 mg, 7.5 mol %) intoluene was heated at 100° C. for 10 minutes. A solution of the productof Step 3 (4-[(4-iodophenyl)oxy]-1-(1-methylethyl)piperidine) (1 g, 2.9mmol) and 1,1-dimethylethyl 1-piperazinecarboxylate (647 mg, 3.5 mmol)in toluene (10 ml) was added followed by sodium tert-butoxide (390 mg,4.4 mmol). This mixture was heated at 100° C. for 3 hours and filteredthrough kieselghur. The filtrate was evaporated and purified on a silicagel eluting with a mixture of 0.88 ammoniasolution:methanol:dichloromethane (0.3:2.7:97) to furnish the titlecompound (770 mg, 66%) MS (ES+) m/e 404 [M+H]⁺.

Step 5: 1-(4-{[1-(1-Methylethyl)-4-piperidinyl]oxy}phenyl)piperazine

A solution of the product of Step 5 (1,1-dimethylethyl4-(4-{[1-(1-methylethyl)-4-piperidinyl]oxy}phenyl)-1-piperazinecarboxylate)(750 mg, 1.86 mmol) in trifluoroacetic acid (4 ml) was stirred at roomtemperature for 30 minutes. The solvent was removed by evaporation andthe residue purified on SCX ion exchange resin eluting with methanol andthen 10% of 0.88 ammonia solution in methanol to furnish the titlecompound (514 mg, 91%)

MS (ES+) m/e 304 [M+H]⁺.

Step 6:1-(4-{[1-(1-Methylethyl)-4-piperidinyl]oxy}phenyl)-4-(tetrahydro-2H-pyran-4-ylcarbonyl)piperazine

A mixture of polymer bound cyclohexyl carbodiimide (460 mg of 1.9 mmol/gresin), tetrahydro-2H-pyran-4-carboxylic acid (111 mg, 0.86 mmol) and1H-1,2,3-benzotriazol-1-ol (116 mg, 0.86 mmol) in dichloromethane (10ml). After 20 minutes the product of Step 5(1-(4-{[1-(1-methylethyl)-4-piperidinyl]oxy}phenyl)piperazine) (128 mg,0.46 mmol) was added and the mixture stirred for 60 minutes. The mixturewas evaporated and the residue was purified on silica gel eluting with amixture of 0.88 ammonia solution:methanol:dichloromethane (0.3:2.7:97)to furnish the title compound (134 mg, 75%)

MS (ES+) m/e 416 [M+H]⁺.

EXAMPLES 264-268

Examples 264 to 268 were prepared in the same manner as Example 263using the appropriate acid highlighted in the table below:

MS (ES+) m/e Compound Acid [M + H]⁺. 4-{[4-(4-{[1-(1-Methylethyl}4-4-cyanobenzoic acid 433 piperidinyl]oxy}phenyl)-1-piperazinyl]carbonyl}benzonitrile (E264) 1-(4-{[1-(1-Methylethyl)-4-Pyridine-4-carboxylic 409 piperidinyl]oxy}phenyl)-4-(4- acidpyridinylcarbonyl)piperazine (E265) 1-(4-{[1-(1-Methylethyl)-4-4-(methylsulfonyl) 486 piperidinyl]oxy}phenyl)-4-{[4- benzoic acid(methylsulfonyl)phenyl]carbonyl}piperazine (E266)1-[(1,1-Dioxidotetrahydro-2H-thiopyran-4- tetrahydro-2H- 464yl)carbonyl]-4-(4-{[1-(1-methylethyl)-4- thiopyran-4-carboxylicpiperidinyl]oxy}phenyl)piperazine (E267) acid 1,1-dioxide1-(4-{[1-(1-Methylethyl)-4- 4-(1-pyrrolidinyl 505piperidinyl]oxy}phenyl)-4-{[4-(1- carbonyl)benzoic acidpyrrolidinylcarbonyl)phenyl]carbonyl} (J.Med. Chem., 46(10), piperazine(E268) 1845-1857, 2003)

EXAMPLE 2694-{[4-(4-{[3-(1-Piperidinyl)propyl]oxy}phenyl)-1-piperazinyl]carbonyl}morpholine(E269)

Step 1: 4-(4-{[3-(1-Piperidinyl)propyl]oxy}phenyl)-1-piperazinecarbonylchloride hydrochloride salt

A solution of 1-(4-{[3-(1-piperidinyl)propyl]oxy}phenyl)piperazine (D11)(524 mg, 1.73 mmol) in dichloromethane (10 ml) was added drop-wise to 2Msolution of phosgene in toluene (1.8 ml). The mixture was stirred atroom temperature for 60 minutes and the solvent was removed byevaporation to give a white powder (680 mg) NMR (DMSO) δ 1.4 (2H, m),1.75 (4H, m), 2.2 (2H, m), 2.88 (2H, m), 3.1-3.9 (12H, m), 4.06 (2H, m),6.89 (2H, m), 7.01 (2H, m), 9.97 (H, m)

Step 2:4-{[4-(4-{[3-(1-Piperidinyl)propyl]oxy}phenyl)-1-piperazinyl]carbonyl}morpholine

Morpholine (75 μl, 1.1 mmol) was added to a mixture of the product ofStep 1 (4-(4-{[3-(1-piperidinyl)propyl]oxy}phenyl)-1-piperazinecarbonylchloride hydrochloride salt) (170 mg, 0.42 mmol) and triethylamine (126μl, 0.88 mmol) in dichloromethane (5 ml). After 60 minutes the mixturewas evaporated and purified on a silica gel eluting with mixture ofmethanol: 0.88 ammonia: methanol: dichloromethane 0.2:2.8:98) solutionto give a white solid (141 mg, 81%) MS (ES+) m/e 417 [M+H]⁺.

EXAMPLES 270-282

Examples 270 to 282 were prepared in the same manner as Example 269using the appropriate amine highlighted in the table below.

MS (ES+) m/e Compound Amine [M + H]⁺.1-(4-{[3-(1-Piperidinyl)propyl]oxy}phenyl)-4-(1- Pyrrolidine 401pyrrolidinylcarbonyl)piperazine (E270)1-(1-Piperidinylcarbonyl)-4-(4-{[3-(1- Piperidine 415piperidinyl)propyl]oxy}phenyl)piperazine (E271)4-(4-{[3-(1-Piperidinyl)propyl]oxy}phenyl)-1- Ammonia 347piperazinecarboxamide (E272)4-{[4-(4-{[3-(1-Piperidinyl)propyl]oxy}phenyl)-1- Thiomorpholine 433piperazinyl]carbonyl}thiomorpholine (E273)4-{[4-(4-{[3-(1-Piperidinyl)propyl]oxy}phenyl)-1- thiomorpholine 465piperazinyl]carbonyl}thiomorpholine 1,1-dioxide (E274) 1,1-dioxide4-(4-{[3-(1-Piperidinyl)propyl]oxy}phenyl)-N- tetrahydro-2H- 431(tetrahydro-2H-pyran-4-yl)-1-piperazinecarboxamide pyran-4-amine (E275)1-{[(2R,6S)-2,6-Dimethyl-1-piperidinyl]carbonyl}-4-(4- (2R,6S)-2,6- 443{[3-(1-piperidinyl)propyl]oxy}phenyl)piperazine (E276)dimethylpiperidine 1-{[4-(4-{[3-(1-Piperidinyl)propyl]oxy}phenyl)-1-4-piperidine 458 piperazinyl]carbonyl}-4-piperidinecarboxamide (E277)carboxamide 1-{[(2R,5S)-2,5-Dimethyl-1-pyrrolidinyl]carbonyl}-4-(4-(2R,5S)-2,5- 429 {[3-(1-piperidinyl)propyl]oxy}phenyl)piperazine (E278)dimethyl pyrrolidine 1-[(2-Phenyl-1-pyrrolidinyl)carbonyl]-4-(4-{[3-(1-2-phenyl 477 piperidinyl)propyl]oxy}phenyl)piperazine (E279) pyrrolidine1-[(3-Phenyl-1-pyrrolidinyl)carbonyl]-4-(4-{[3-(1- 3-phenyl 477piperidinyl)propyl]oxy}phenyl)piperazine (E280) pyrrolidine4-(4-{[3-(1-Piperidinyl)propyl]oxy}phenyl)-N-6- 6-quinolinamine 474quinolinyl-1-piperazinecarboxamide (E281) N-(4-Cyanophenyl)-4-(4-{[3-(1-4-amino 448 piperidinyl)propyl]oxy}phenyl)-1- benzonitrilepiperazinecarboxamide (E282)

EXAMPLE 283 1,1-Dimethylethyl4-{[4-(4-{[3-(1-piperidinyl)propyl]oxy}phenyl)-1-piperazinyl]carbonyl}-1-piperazinecarboxylate(E283)

A solution of 1-(4-{[3-(1-piperidinyl)propyl]oxy}phenyl)piperazine (D11)(1.8 g, 5.94 mmol) in dichloromethane 15 ml) was added to a 2M solutionof phosgene in toluene (6 ml) and stirrer for 60 minutes. The solventwas removed by evaporation and the residue dissolved in dichloromethane(30 ml). Triethylamine (1.7 ml, 11.9 mmol) was added followed by1,1-dimethylethyl 1-piperazinecarboxylate (1.2 g, 6.5 mmol) and themixture stirred for 90 minutes. The solvent was removed by evaporationand the residue purified on silica gel eluting with a mixture of 0.88ammonia solution:methanol:dichloromethane (0.5:4.5:95) to furnish thetitle compound (1.13 g, 37%) MS (ES+) m/e 516 [M+H]⁺.

EXAMPLE 2841-(1-piperazinylcarbonyl)-4-(4-{[3-(1-piperidinyl)propyl]oxy}phenyl)piperazine(E284)

A solution of 1,1-dimethylethyl4-{[4-(4-{[3-(1-piperidinyl)propyl]oxy}phenyl)-1-piperazinyl]carbonyl}-1-piperazinecarboxylate(E283) (1.13 g, 2.19 mmol) in trifluoroacetic acid (5 ml) anddichloromethane (5 ml) was stirred at room temperature for 90 minutes.The solvent was removed by evaporation and the residue purified an SCXion exchange resin eluting with methanol and then a mixture of 0.88ammonia solution:methanol (1:9) to furnish the title compound (854 mg,94%) MS (ES+) m/e 416 [M+H]⁺.

EXAMPLE 2851-(2-Methylpropanoyl)-4-{[4-(4-{[3-(1-piperidinyl)propyl]oxy}phenyl)-1-piperazinyl]carbonyl}piperazine(E285)

2-methylpropanoyl chloride (30 μl, 1.2 mmol) was added to a stirringmixture of1-(1-piperazinylcarbonyl)-4-(4-{[3-(1-piperidinyl)propyl]oxy}phenyl)piperazine(E284) (100 mg, 0.24 mmol) and triethylamine (37 μl, 0.26 mmol) indichloromethane (2 ml). The resulting mixture was stirred at roomtemperature for 60 minutes. This was evaporated and passed through anSCX ion exchange resin eluting with methanol and then a mixture of 0.88ammonia solution:methanol (1:9). The basic fractions were evaporated andthe residue purified on silica gel eluting with a mixture of 0.88ammonia solution:methanol:dichloromethane (0.5:4.5:95) to furnish thetitle compound (50 mg, 43%)

MS (ES+) m/e 486 [M+H]⁺.

EXAMPLES 286-291

Examples 286 to 291 were prepared in the same manner as Example 285using the appropriate acid chloride:

MS (ES+) m/e Compound Acid Chloride [M + H]⁺.1-(Cyclopropylcarbonyl)-4-{[4-(4-{[3-(1- cyclopropanecarbonyl 484piperidinyl)propyl]oxy}phenyl)-1- chloridepiperazinyl]carbonyl}piperazine (E286)1-(Cyclobutylcarbonyl)-4-{[4-(4-{[3-(1- cyclobutanecarbonyl 497piperidinyl)propyl]oxy}phenyl)-1- chloridepiperazinyl]carbonyl}piperazine (E287)1-(Cyclopentylcarbonyl)-4-{[4-(4-{[3-(1- cyclopentanecarbonyl 512piperidinyl)propyl]oxy}phenyl)-1- chloridepiperazinyl]carbonyl}piperazine (E288)1-(Cyclohexylcarbonyl)-4-{[4-(4-{[3-(1- cyclohexanecarbonyl 526piperidinyl)propyl]oxy}phenyl)-1- chloridepiperazinyl]carbonyl}piperazine (E289)1-(4-{[3-(1-Piperidinyl)propyl]oxy}phenyl)-4-{[4- tetrahydro-2H-pyran-528 (tetrahydro-2H-pyran-4-ylcarbonyl)-1- 4-carbonyl chloridepiperazinyl]carbonyl}piperazine (E290)1-[(4-Chlorophenyl)carbonyl]-4-{[4-(4-{[3-(1- 4-chlorobenzoyl 555piperidinyl)propyl]oxy}phenyl)-1- chloridepiperazinyl]carbonyl}piperazine (E291 )

EXAMPLE 2924-[(4-{4-[(1-Cyclobutyl-4-piperidinyl)oxy]phenyl}-1-piperazinyl)carbonyl]morpholine(E292)

Step 1: Phenylmethyl4-{4-[(1-{[(1,1-dimethylethyl)oxy]carbonyl}-4-piperidinyl)oxy]phenyl}-1-piperazinecarboxylate

A mixture of palladium acetate (300 mg, 5 mol %) and2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (1.3 g, 7.5 mol %) intoluene was heated at 100° C. for 10 minutes. A solution of the productof Example 263, step 1 (1,1-dimethylethyl4-[(4-iodophenyl)oxy]-1-piperidinecarboxylate) (13 g, 59.5 mmol) andphenylmethyl 1-piperazinecarboxylate (20 g, 49.6 mmol) in toluene (120ml) was added followed by sodium tert-butoxide (7.1 g, 64.5 mmol). Thismixture was heated at 100° C. for 15 minutes and filtered throughkieselghur. The filtrate was evaporated and purified on silica geleluting with a mixture of hexane:ethyl:acetate (2:1) to furnish thetitle compound (6.4 g, 26%) MS (ES+) m/e 496 [M+H]⁺.

Step 2: Phenylmethyl4-[4-(4-piperidinyloxy)phenyl]-1-piperazinecarboxylate

A solution of the product from step 1 (phenylmethyl4-{4-[(1-{[(1,1-dimethylethyl)oxy]carbonyl}-4-piperidinyl)oxy]phenyl}-1-piperazinecarboxylate)(2 g, 4 mmol) in trifluoroacetic acid (5 ml) and dichloromethane (5 ml)was stirred at room temperature for 45 minutes. The solvent was removedby evaporation and the residue purified an SCX ion exchange resineluting with methanol and then a mixture of 0.88 ammoniasolution:methanol (1:9). methanol. The basic fractions were then reducedin vacuo to furnish the title compound (1.53 mg, 97%) MS (ES+) m/e 396[M+H]⁺.

Step 3: Phenylmethyl4-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-1-piperazinecarboxylate

Sodium triacetoxyborohydride (1.64 g, 7.74 mmol) was added to a solutionof the product of step 2 (phenylmethyl4-[4-(4-piperidinyloxy)phenyl]-1-piperazinecarboxylate) (1.53 g, 3.87mmol) and cyclobutanone (578 μl, 7.74 mmol) in dichloromethane (15 ml).After 2 hours, methanol was added and the mixture evaporated. Theresidue was passed through an SCX ion exchange resin eluting withmethanol and then a mixture of 0.88 ammonia solution:methanol (1:9). Thebasic fractions were evaporated and the residue purified on silica geleluting with a mixture of 0.88 ammonia solution:methanol:dichloromethane(0.5:4.5:95) to furnish the title compound (1.35 g, 78%) MS (ES+) m/e450 [M+H]⁺.

Step 4: 1-{4-[(1-Cyclobutyl-4-piperidinyl)oxy]phenyl}piperazine

A solution of phenylmethyl4-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-1-piperazinecarboxylate(1.35 g, 3 mmol) in absolute ethanol 20 ml was hydrogenated at roomtemperature and pressure over a 50% wet paste of 10% palladium on carbon(500 mg). After 18 hours the catalyst was removed by filtration and thefiltrate evaporated to give the title compound (889 mg, 94%) MS (ES+)m/e 316 [M+H]⁺.

Step 5:4-[(4-{4-[(1-Cyclobutyl-4-piperidinyl)oxy]phenyl}-1-piperazinyl)carbonyl]morpholine

4-morpholinecarbonyl chloride (78 mg, 0.53 mmol) was added to a mixtureof the product from step 4(1-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}piperazine) (150 mg, 0.48mmol) and polymer bound diethylamine resin (300 mg of 3.2 mmol/g) indichloromethane (5 ml). After 2 hours the mixture was filtered and thefiltrate evaporated. The residue was residue purified on a silica onsilica gel eluting with a mixture of 0.88 ammoniasolution:methanol:dichloromethane (0.5:4.5:95) to furnish the titlecompound (121 mg, 58%)

MS (ES+) m/e 429 [M+H]⁺.

EXAMPLE 2934-{[4-(4-{[1-(1-Methylethyl)-4-piperidinyl]oxy}phenyl)-1-piperazinyl]carbonyl}morpholine(E293)

A solution of the product of Example 263, step 5(1-(4-{[1-(1-methylethyl)-4-piperidinyl]oxy}phenyl)piperazine) (200 mg,0.66 mmol) was added to a 2M solution of phosgene in toluene (1.3 ml)and the mixture stirred for 30 minutes. The solvent was removed byevaporation and the residue dissolved in dichloromethane (5 ml).Morpholine (75 μl, 1.1 mmol) followed by triethylamine (126 μl, 0.88mmol) were then added. After 60 minutes the mixture was evaporated andpurified on a silica gel eluting with a mixture of 0.88 ammoniasolution:methanol:dichloromethane (0.3:2.7:97) to furnish the titlecompound (177 mg, 65%) MS (ES+) m/e 417 [M+H]⁺.

EXAMPLE 2941-(4-{[1-(1-Methylethyl)-4-piperidinyl]oxy}phenyl)-4-(1-piperidinylcarbonyl)piperazine(E294)

Example 294 was Prepared in the Same Manner as Example 293 fromPiperidine.

MS (ES+) m/e 415 [M+H]⁺.

EXAMPLE 2951-[4-({[1-(1-Methylethyl)-4-piperidinyl]methyl}oxy)phenyl]-4-(phenylcarbonyl)piperazine(E295)

Step 1: 1,1-Dimethylethyl 4-(hydroxymethyl)-1-piperidinecarboxylate

1-{[(1,1-dimethylethyl)oxy]carbonyl}-4-piperidinecarboxylic acid (2.0 g,8.73 mmol) was dissolved in dry tetrahydrofuran (20 ml), cooled in anice bath and treated with 1M borane-tetrahydrofuran solution (17.46 ml,17.46 mmol) under argon. The mixture was allowed to warm to ambienttemperature and stirred under argon for 4 hours. A solution of methanol(5 ml) in tetrahydrofuran (10 ml) was added followed by methanol (4 ml)and water (2 ml). The solvent was removed in vacuo and the residuedissolved in ethyl acetate and washed with saturated sodium bicarbonatesolution (×2). The organic layer was separated, dried under magnesiumsulphate and evaporated in vacuo to give the title compound (1.83 g). ¹HNMR (CDCl₃) δ 4.18-4.10 (2H, m), 3.51-3.50 (2H, m), 2.72-2.68 (2H, m),1.75-1.69 (2H, m), 1.62 (1H, m), 1.46 (9H, s), 1.20-1.10 (2H, m).

Step 2: 1,1-Dimethylethyl 4-(iodomethyl)-1-piperidinecarboxylate

Triphenylphosphine (2.79 g, 10.6 mmol) was added to a mixture of iodine(2.59 g, 10.2 mmol) in toluene (90 ml). After 5 minutes, pyridine (1.65ml, 20.4 mmol) followed by the product from Step 1 was added. Theresulting mixture was heated under reflux for 3 hours. The cooledreaction mixture was filtered and the filtrate was washed with saturatedsodium thiosulfate and brine, dried under magnesium sulphate, filteredand concentrated in vacuo. The residue was purified by silica gelchromatography eluting with a mixture of ethyl acetate:hexane (1:9) togive the title compound (1.83 g). ¹H NMR (CDCl₃) δ 4.18-4.10 (2H, m),3.11-3.09 (2H, d), 2.72-2.65 (2H, m), 1.88-1.82 (2H, m), 1.62 (1H, m),1.46 (9H, s), 1.20-1.11 (2H, m).

Step 3: 4[4-(Phenylcarbonyl)-1-piperazinyl]phenol

4-(1-piperazinyl)phenol (4.0 g, 22.5 mmol) was dissolved in drydichloromethane (50 ml), treated with triethylamine (3.4 ml, 24.8 mmol)and benzoyl chloride (2.6 ml, 22.5 mmol) and stirred at ambienttemperature under argon for 2 hours. The solvent was removed in vacuoand the residue dissolved in ethyl acetate. The ethyl acetate layer waswashed with saturated sodium bicarbonate solution, dried under magnesiumsulphate and evaporated in vacuo. The crude product was dissolved inmethanol, treated with potassium carbonate (2 equivalents) and stirredat ambient temperature for 30 minutes. The potassium carbonate wasfiltered and the filtrate evaporated in vacuo. The residue was dissolvedin ethyl acetate, washed with saturated sodium bicarbonate solution,dried under magnesium sulphate and evaporated in vacuo to give the titlecompound (5.27 g). MS (ES+) m/e 283 [M+H]⁺.

Step 4: 1,1-Dimethylethyl4[({4-[4-(phenylcarbonyl)-1-piperazinyl]phenyl}oxy)methyl]-1-piperidinecarboxylate

The product from step 2 (1.83 g, 5.63 mmol), the product from step 3(1.59 g, 5.63 mmol), potassium carbonate (1.86 g, 13.5 mmol) andpotassium iodide (2.24 g, 13.5 mmol) were added together in 2-butanone(70 ml) and the mixture heated under reflux for 24 hours. The mixturewas allowed to cool to room temperature, treated with sodium thiosulfate(1M, 15 ml) and extracted with ethyl acetate. The organic layer wasseparated, washed with water and brine, dried under magnesium sulphateand evaporated in vacuo. The title compound (0.30 g) was obtained bysilica gel chromatography eluting with a mixture of ethyl acetate:hexane(1:1). MS (ES+) m/e 480 [M+H]⁺.

Step 5:1-(Phenylcarbonyl)-4-{4[(4-piperidinylmethyl)oxy]phenyl}piperazine

The product from step 4 (0.30 g, 0.63 mmol) was dissolved indichloromethane (3 ml), treated with trifluoroacetic acid (2 ml) andstirred at room temperature under argon for 2 hours. The solvent wasremoved in vacuo and the residue dissolved in methanol and passed downan SCX ion exchange column (5 g) eluting with methanol followed by amixture of 0.880 ammonia:methanol (1:9). The basic fractions werecombined and concentrated in vacuo to afford the title compound (0.1 g);MS (ES+) m/e 380 [M+H]⁺.

Step 6:1-[4-({[1-(1-Methylethyl)-4-piperidinyl]methyl}oxy)phenyl]-4-(phenylcarbonyl)piperazine

The product of step 5 (90 mg, 0.24 mmol) in dry dichloromethane (4 ml)was treated with acetone (0.06 ml, 0.72 mmol) and glacial acetic acid (1drop) and stirred at ambient temperature for 15 minutes. Sodiumtriacetoxyborohydride (152 mg, 0.72 mmol) was added and the reactionmixture stirred at ambient temperature under argon for 36 hours. Thereaction mixture was diluted with methanol and passed down an SCX ionexchange column (5 g) eluting with methanol followed by a mixture of0.880 ammonia:methanol (1:9). The basic fractions were combined andconcentrated in vacuo to afford the title compound (98 mg); MS (ES+) m/e422 [M+H]⁺.

EXAMPLE 2961-[4-({[(35)-1-(1-Methylethyl)-3-piperidinyl]methyl}oxy)phenyl]-4-(phenylcarbonyl)piperazine(E296)

Step 1: 1,1-Dimethylethyl (3S)-3-(hydroxymethyl)-1-piperidinecarboxylate

The title compound was prepared from(3S)-1-{[(1,1-dimethylethyl)oxy]carbonyl}-3-piperidinecarboxylic acidusing the method of Example 295 step 1. ¹H NMR (CDCl₃) δ 3.99-3.58 (3H,m), 3.50 (1H, m), 3.22-2.95 (1H, m), 2.80-2.52 (1H, m), 1.87-1.52 (3H,m), 1.46 (9H, s), 1.32-1.12 (1H, m), 0.95-0.92 (1H, q).

Step 2: 1,1-Dimethylethyl (3S)-3-(iodomethyl)-1-piperidinecarboxylate

The title compound was prepared from the product of step 1 using themethod of Example 295 step 2. ¹H NMR (CDCl₃) δ 4.11-3.98 (1H, m),3.87-3.82 (1H, m), 3.09-2.08 (2H, d), 2.85-2.78 (2H, m), 1.93-1.91 (1H,m), 1.66-1.62 (2H, m), 1.47 (10H, s), 1.30-1.22 (1H, m).

Step 3: 1,1-Dimethylethyl(3S)-3-[({4-[4-(phenylcarbonyl)-1-piperazinyl]phenyl}oxy)methyl]-1-piperidinecarboxylate

The title compound was prepared from the product of step 2 and theproduct of Example 295 Step 3 using the method of Example 295 Step 4. MS(ES+) m/e 480 [M+H]⁺

Step 4:1-(Phenylcarbonyl)-4-(4-{[(3S)-3-piperidinylmethyl]oxy}phenyl)piperazine

The title compound was prepared from the product of step 3 using themethod of Example 295 Step 5. MS (ES+) m/e 380 [M+H]⁺

Step 5:1-[4-({[(3S)-1-(1-Methylethyl)-3-piperidinyl]methyl}oxy)phenyl]-4-(phenylcarbonyl)piperazine

The title compound was prepared from the product of step 4 and acetoneusing the method of Example 295 Step 6. MS (ES+) m/e 422 [M+H]⁺

EXAMPLES 297-299

The following examples were prepared from the product of Example 296Step 4 using the method of Example 295 Step 6 with the appropriateketone or aldehyde as indicated in the table below.

MS (ES+) Ketone or m/e Example Aldehyde [M + H]⁺1-[4-({[(3S)-1-Cyclopentyl-3- Cyclopentanone 448piperidinyl]methyl}oxy)phenyl]-4- (phenylcarbonyl)piperazine (E297)1-[4-({[(3S)-1-(Cyclopropylmethyl)-3- Cyclopropane 434piperidinyl]methyl}oxy)phenyl]-4- carboxaldehyde(phenylcarbonyl)piperazine (E298) 1-[4-({[(3S)-1-Ethyl-3- Acetaldehyde408 piperidinyl]methyl}oxy)phenyl]- 4-(phenylcarbonyl)piperazine (E299)

EXAMPLE 3001-[4-({[(3R)-1-(1-Methylethyl)-3-piperidinyl]methyl}oxy)phenyl]-4-(phenylcarbonyl)piperazine(E300)

Step 1: 1,1-Dimethylethyl (3R)-3-(hydroxymethyl)-1-piperidinecarboxylate

The title compound was prepared from(3R)-1-{[(1,1-dimethylethyl)oxy]carbonyl}-3-piperidinecarboxylic acidusing the method of Example 295 step 1. ¹H NMR (CDCl₃) δ 3.99-3.58 (3H,m), 3.50 (1H, m), 3.22-2.95 (1H, m), 2.80-2.52 (1H, m), 1.87-1.52 (3H,m), 1.46 (9H, s), 1.32-1.12 (1H, m), 0.95-0.92 (1H, q).

Step 2: 1,1-Dimethylethyl (3R)-3-(iodomethyl)-1-piperidinecarboxylate

The title compound was prepared from the product of step 1 using themethod of Example 295 step 2. ¹H NMR (CDCl₃) δ 4.11-3.98 (1H, m),3.87-3.82 (1H, m), 3.09-2.08 (2H, d), 2.85-2.78 (2H, m), 1.93-1.91 (1H,m), 1.66-1.62 (2H, m), 1.47 (10H, s), 1.30-1.22 (1H, m).

Step 3: 1,1-Dimethylethyl(3R)-3-[({4-[4-(phenylcarbonyl)-1-piperazinyl]phenyl}oxy)methyl]-1-piperidinecarboxylate

The title compound was prepared from the product of step 2 and theproduct of Example 295 Step 3 using the method of Example 295 Step 4. MS(ES+) m/e 480 [M+H]⁺

Step 4:1-(Phenylcarbonyl)-4-(4-{[(3R)-3-piperidinylmethyl]oxy}phenyl)piperazine

The title compound was prepared from the product of step 3 using themethod of Example 295 Step 5. MS (ES+) m/e 380 [M+H]⁺

Step 5:1-[4-({[(3R)-1-(1-Methylethyl)-3-piperidinyl]methyl}oxy)phenyl]-4-(phenylcarbonyl)piperazine

The title compound was prepared from the product of step 4 and acetoneusing the method of Example 295 Step 6. MS (ES+) m/e 422 [M+H]⁺

EXAMPLES 301-302

The following examples were prepared from the product of Example 300Step 4 using the method of Example 295 Step 6 using the appropriatealdehyde or ketone as indicated.

MS (ES+) Ketone or m/e Example Aldehyde [M + H]⁺1-[4-({[(3R)-1-Cyclopentyl-3- Cyclopentanone 448piperidinyl]methyl}oxy)phenyl]-4- (phenylcarbonyl)piperazine (E301)1-[4-({[(3R)-1-(Cyclopropylmethyl)-3- Cyclopropane 434piperidinyl]methyl}oxy)phenyl]-4- carboxaldehyde(phenylcarbonyl)piperazine (E302)

EXAMPLE 3034-({4-[4-({[(3S)-1-Cyclopentyl-3-piperidinyl]methyl}oxy)phenyl]-1-piperazinyl}carbonyl)benzonitrile(E303)

Step 1: 4-{[4-(4-Hydroxyphenyl)-1-piperazinyl]carbonyl}benzonitrile

4-Cyanobenzoic acid (6.2 g, 42.2 mmol), 1,3-dicyclohexylcarbodiimide(8.7 g, 42.2 mmol) and 1-hydroxybenzotriazole hydrate (5.7 g, 42.2 mmol)were added to a suspension of 4-(1-piperazinyl)phenol (5.0 g, 28.1 mmol)in dry dichloromethane (50 ml). The mixture was stirred at ambienttemperature for 2 hours, diluted with dichloromethane and washed withsaturated sodium bicarbonate solution. The organic layer was separated,dried under magnesium sulphate and evaporated in vacuo. The residue waspurified by column chromatography eluting with a mixture of ethylacetate:hexane (1:1) to give the title compound (2.2 g).

MS (ES+) m/e 308 [M+H]⁺.

Step 2: 1,1-Dimethylethyl(3S)-3-{[(4-{4-[(4-cyanophenyl)carbonyl]-1-piperazinyl}phenyl)oxy]methyl}-1-piperidinecarboxylate

The title compound was prepared from the product of step 1 and theproduct of Example 296 Step 2 using the method of Example 295 Step 4. MS(ES+) m/e 505 [M+H]⁺

Step 3:4-{[4-(4-{[(3S)-3-Piperidinylmethyl]oxy}phenyl)-1-piperazinyl]carbonyl}benzonitrile

The title compound was prepared from the product of step 2 using themethod of Example 295 Step 5. MS (ES+) m/e 405 [M+H]⁺

Step 4:4-({4-[4-({[(3S)-1-Cyclopentyl-3-piperidinyl]methyl}oxy)phenyl]-1-piperazinyl}carbonyl)benzonitrile

The title compound were prepared from the product of step 3 andcyclopentanone using the method of Example 295 step 6. MS (ES+) m/e 473[M+H]⁺

EXAMPLE 3041-(Phenylcarbonyl)-4-(4-{[2-(1-piperidinyl)ethyl]oxy}phenyl)piperazine(E304)

Step 1: 1-{4-[(2-Bromoethyl)oxy]phenyl}-4-(phenylcarbonyl)piperazine

The product from Example 295 Step 3 (1.0 g, 3.55 mmol) was dissolved in2-butanone (20 ml), treated with 1,2-dibromoethane (0.46 ml, 5.32 mmol)and potassium carbonate (0.73 g, 5.32 mmol) and the resulting mixturewas heated under reflux for 18 hours. The reaction mixture was allowedto cool to ambient temperature, diluted with water, made basic byaddition of aqueous sodium hydroxide solution (2M) and extracted withethyl acetate. The ethyl acetate layer was separated, dried undermagnesium sulphate and evaporated in vacuo. The residue was purified bysilica gel chromatography eluting with a mixture of ethyl acetate:hexane(1:1) to give the title compound (0.40 g). MS (ES+) m/e 390 [M+H]⁺

Step 2:1-(Phenylcarbonyl)-4-(4-{[2-(1-piperidinyl)ethyl]oxy}phenyl)piperazine

The title compound was prepared from the product of step 1 andpiperidine using the method of Example 295 Step 4. MS (ES+) m/e 394[M+H]⁺

EXAMPLE 3054-({4-[4-{[3-(1-Piperidinyl)propyl]oxy}-2-(trifluoromethyl)phenyl]-1-piperazinyl}carbonyl)benzonitrile(E305)

Step 1: 4-Bromo-3-(trifluoromethyl)phenol

3-(Trifluoromethyl)phenol (1.88 ml, 15.4 mmol) was dissolved in aceticacid (4 ml) and treated with bromine (2.7 g, 16.9 mmol) dropwise. Theresulting mixture was stirred at ambient temperature for 2 hours, pouredinto water (15 ml) and extracted with dichloromethane (×3). Thedichloromethane layers were combined, washed with saturated sodiumbicarbonate solution, dried under magnesium sulphate and evaporated invacuo. The residue was purified by silica gel chromatography elutingwith a mixture of hexane:dichloromethane (1:4) to give the titlecompound (0.73 g). ¹H NMR (CDCl₃) δ 7.55-7.53 (1H, d), 7.19-7.18 (1H,d), 6.89-6.86 (1H, dd), 5.51 (1H, s).

Step 2: 1-(3-{[4-Bromo-3-(trifluoromethyl)phenyl]oxy}propyl)piperidine

The product from step 1 was dissolved in 2-butanone (30 ml), treatedwith 1-(3-chloropropyl)piperidine hydrochloride (0.72 g, 3.63 mmol),potassium carbonate (1.17 g, 8.48 mmol) and sodium iodide (0.15 g, 0.91mmol) and heated under reflux for 18 hours. The mixture was allowed tocool to ambient temperature, diluted with ethyl acetate and washed withwater. The organic layer was separated, dried under magnesium sulphateand evaporated in vacuo. The residue was purified by silica gelchromatography eluting with a mixture of 0.880ammonia:methanol:dichloromethane (0.5:4.5:95) to give the title compound(0.76 g). MS (ES+) m/e 367 [M+H]⁺

Step 3: 1,1-Dimethylethyl4-[4-{[3-(1-piperidinyl)propyl]oxy}-2-(trifluoromethyl)phenyl]-1-piperazinecarboxylate

An oven dried 50 ml round bottomed flask was charged with palladiumacetate (23 mg, 0.10 mmol),rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (97 mg, 0.16 mmol) anddry toluene (4 ml). The mixture was heated under argon at 100° C. for 3minutes after which a dark purple solution was obtained. The productfrom step 2 (0.76 g, 2.08 mmol) in toluene (2 ml), 1,1-dimethylethyl1-piperazinecarboxylate (0.46 g, 2.49 mmol) in toluene (2 ml) andpotassium tert-butoxide (0.30 g, 3.12 mmol) were added and the mixtureheated at 100° C. for 5 hours. The reaction mixture was allowed to cool,acidified with acetic acid and passed down an SCX ion exchange column(10 g) eluting with methanol followed by a mixture of 0.880ammonia:methanol (1:9). The basic fractions were combined and evaporatedin vacuo. The residue was purified by silica gel chromatography elutingwith a mixture of 0.880 ammonia/methanol/dichloromethane (0.7:6.3:93) togive the title compound (0.49 g).

MS (ES+) m/e 472 [M+H]⁺

Step 4:1-[4-{[3-(1-Piperidinyl)propyl]oxy}-2-(trifluoromethyl)phenyl]piperazine

The title compound was prepared from the product of step 3 using theprocedure of Example 295 Step 5. MS (ES+) m/e 372 [M+H]⁺

Step 5:4-({4-[4-{[3-(1-Piperidinyl)propyl]oxy}-2-(trifluoromethyl)phenyl]-1-piperazinyl}carbonyl)benzonitrile

4-Cyanobenzoic acid (123 mg, 0.84 mmol), polymer bound1,3-dicyclohexylcarbodiimide (1.9 mmol/g, 442 mg, 0.84 mmol) and1-hydroxybenzotriazole hydrate (113 mg, 0.84 mmol) were stirred in drydichloromethane (5 ml) for 30 minutes. The product from step 4 (154 mg,0.42 mmol) was added and the mixture stirred at ambient temperature for2 hours. The reaction mixture was diluted with methanol and passed downan SCX ion exchange column (5 g) eluting with methanol followed by amixture of 0.880 ammonia:methanol (1:9). The basic fractions werecombined and evaporated in vacuo to give the title compound (0.199 g).

MS (ES+) m/e 501 [M+H]⁺.

EXAMPLE 3062-[4-(Phenylcarbonyl)-1-piperazinyl]-5-{[3-(1-piperidinyl)propyl]oxy}benzonitrile(E306)

Step 1: 2-Bromo-5-hydroxybenzonitrile

3-Hydroxybenzonitrile (2.0 g, 16.8 mmol) was dissolved in acetonitrile(20 ml) and cooled to 20° C. Tetrafluoroboric acid diethyl ether complex(2.3 ml, 16.8 mmol) followed by N-bromosuccinimide (3.0 g, 16.8 mmol)were added and the mixture allowed to warm to ambient temperature. Theresulting mixture was stirred for 5 hours, treated with aqueous sodiumhydrogen sulfate solution (38%, 10 ml) and extracted with methyl2-methylpropyl ether (×2). The organic extracts were combined, washedwith water (×2) and brine, dried under magnesium sulphate and evaporatedin vacuo. The residue was purified by silica gel chromatography elutingwith a mixture of methyl 2-methylpropyl ether/dichloromethane (2:98) togive the title compound (1.58 g). MS (ES+) m/e 197 [M−H]⁺

Step 2: 2-Bromo-5-{[3-(1-piperidinyl)propyl]oxy}benzonitrile

The title compound was prepared from the product of step 1 and1-(3-chloropropyl)piperidine hydrochloride using the method of Example305 Step 2. MS (ES+) m/e 324 [M+H]⁺

Step 3: 1,1-Dimethylethyl4-(2-cyano-4-{[3-(1-piperidinyl)propyl]oxy}phenyl)-1-piperazinecarboxylate

The title compound was prepared from the product of step 2 and1,1-dimethylethyl 1-piperazinecarboxylate using the method of Example305 Step 3. MS (ES+) m/e 429 [M+H]⁺

Step 4: 2-(1-piperazinyl)-5-{[3-(1-piperidinyl)propyl]oxy}benzonitrile

The title compound was prepared from the product of step 3 using theprocedure of Example 295 Step 5. MS (ES+) m/e 329 [M+H]⁺

Step 5:2-[4-(Phenylcarbonyl)-1-piperazinyl]-5-{[3-(1-piperidinyl)propyl]oxy}benzonitrile

The title compound was prepared from the product of step 4 and benzoicacid using the procedure of Example 305 Step 5. MS (ES+) m/e 433 [M+H]⁺

EXAMPLES 307-309

The following examples were prepared from the product of Example 306Step 4 and the appropriate carboxylic acid indicated in table belowusing the method of Example 305 Step 5.

MS (ES+) m/e Example Carboxylic Acid [M + H]⁺2-{4-[(4-Cyanophenyl)carbonyl]-1-piperazinyl}-5- 4-cyano benzoic acid458 {[3-(1-piperidinyl)propyl]oxy}benzonitrile (E307)2-{4-[(4-Fluorophenyl)carbonyl]-1-piperazinyl}-5- 4-fluoro benzoic 451{[3-(1-piperidinyl)propyl]oxy}benzonitrile (E308) acid5-{[3-(1-Piperidinyl)propyl]oxy}-2-(4-{[4-(1- 4-(1-pyrrolidinyl 530pyrrolidinylcarbonyl)phenyl]carbonyl}-1- carbonyl) benzoicpiperazinyl)benzonitrile (E309) acid (J. Med. Chem., 46(10), 1845-1857,2003)

EXAMPLE 3101-(2-Fluoro-4-{[3-(1-piperidinyl)propyl]oxy}phenyl)-4-(phenylcarbonyl)piperazine(E310)

Step 1: 1-{3-[(4-Bromo-3-fluorophenyl)oxy]propyl}piperidine

The title compound was prepared from 4-bromo-3-fluorophenol and1-(3-chloropropyl)piperidine hydrochloride using the method of Example305 Step 2. MS (ES+) m/e 317 [M+H]⁺

Step 2: 1,1-Dimethylethyl4-(2-fluoro-4-{[3-(1-piperidinyl)propyl]oxy}phenyl)-1-piperazinecarboxylate

The title compound was prepared from the product of step 1 and1,1-dimethylethyl 1-piperazinecarboxylate using the method of Example305 Step 3. MS (ES+) m/e 422 [M+H]⁺

Step 3: 1-(2-Fluoro-4-{[3-(1-piperidinyl)propyl]oxy}phenyl)piperazine

The title compound was prepared from the product of step 2 using theprocedure of Example 295 Step 5. MS (ES+) m/e 322 [M+H]⁺

Step 4:1-(2-Fluoro-4-{[3-(1-piperidinyl)propyl]oxy}phenyl)-4-(phenylcarbonyl)piperazine

The title compound was prepared from the product of step 3 and benzoicacid using the procedure of Example 305 Step 5. MS (ES+) m/e 426 [M+H]⁺

EXAMPLES 311-313

The following examples were prepared from the product of Example 310Step 3 and the appropriate carboxylic acid indicated in the table belowusing the method of Example 305 Step 5.

MS (ES+) m/e Example Carboxylic Acid [M + H]⁺4-{[4-(2-Fluoro-4-{[3-(1-piperidinyl)propyl]oxy}phenyl)-1-4-cyanobenzoic 451 piperazinyl]carbonyl}benzonitrile (E311) acid1-[(4-Fluorophenyl)carbonyl]-4-(2-fluoro-4-{[3-(1- 4-fluorobenzoic 444piperidinyl)propyl]oxy}phenyl)piperazine (E312) acid1-(2-Fluoro-4-{[3-(1-piperidinyl)propyl]oxy}phenyl)-4-{[4-4-(1-pyrrolidinyl 523 (1-pyrrolidinylcarbonyl)phenyl]carbonyl}piperazine(E313) carbonyl) benzoic acid (J. Med. Chem., 46(10), 1845-1857, 2003)

EXAMPLE 3144-{[4-(2-Fluoro-4-{[3-(1-piperidinyl)propyl]oxy}phenyl)-1-piperazinyl]carbonyl}morpholine(E314)

The product from Example 310 step 3 (150 mg, 0.47 mmol) was dissolved indry dichloromethane (5 ml), treated with diethylaminomethyl polystyrene(3.2 mmol/g, 294 mg, 0.94 mmol) and morpholine carbonyl chloride (0.11ml, 0.94 mmol) and stirred at ambient temperature under argon for 1hour. The reaction mixture was diluted with methanol and passed down anSCX ion exchange column (5 g) eluting with methanol followed by amixture of 0.880 ammonia:methanol (1:9). The basic fractions werecombined and evaporated in vacuo. The residue was purified by columnchromatography eluting with a mixture of 0.880ammonia:methanol:dichloromethane (0.5:4.5:95) to give the title compound(84 mg).

MS (ES+) m/e 435 [M+H]⁺

EXAMPLE 3154-{[4-(2-Fluoro-4-{[1-(1-methylethyl)-4-piperidinyl]oxy}phenyl)-1-piperazinyl]carbonyl}morpholine(E315)

Step 1: 1,1-Dimethylethyl4-[(4-bromo-3-fluorophenyl)oxy]-1-piperidinecarboxylate

4-Bromo-3-fluorophenol (5.0 g, 26.2 mmol) was dissolved in drytetrahydrofuran (100 ml) and treated with 1,1-dimethylethyl4-hydroxy-1-piperidinecarboxylate (6.3 g, 31.4 mmol), triphenylphosphine(8.2 g, 31.4 mmol) and di-t-butylazodicarboxylate (7.2 g, 31.4 mmol).The resulting mixture was stirred at ambient temperature under argon for18 hours and the solvent removed in vacuo. The residue was trituratedwith a mixture of ethyl acetate/hexane (1:9), the white solid filteredand the filtrate purified by silica gel chromatography eluting withethyl acetate:hexane (1:9) to give the title compound (4.67 g). MS (ES+)m/e 375 [M+H]⁺

Step 2: 4-[(4-Bromo-3-fluorophenyl)oxy]piperidine

The product from step 1 (4.67 g, 12.5 mmol) was dissolved in drydichloromethane (30 ml), treated with trifluoroacetic acid (20 ml) andstirred at ambient temperature for 2 hours. The solvent was removed invacuo and the residue made basic by addition of aqueous sodium hydroxidesolution (2M). The resulting mixture was extracted with dichloromethane(×2). The organic layers were combined, washed with brine, dried undermagnesium sulphate and concentrated in vacuo. The residue was purifiedby column chromatography eluting with a mixture of 0.880ammonia:methanol:dichloromethane (1:9:90) to give the title compound(2.13 g). MS (ES+) m/e 275 [M+H]⁺

Step 3: 4-[(4-Bromo-3-fluorophenyl)oxy]-1-(1-methylethyl)piperidine

The product from step 2 (2.13 g, 7.77 mmol) was dissolved in drydichloromethane (20 ml), treated with acetone (0.86 ml, 11.7 mmol) andacetic acid (2 drops) and stirred for 15 minutes at ambient temperature.Sodium triacetoxyborohydride (2.48 g, 11.7 mmol) was added and themixture stirred at ambient temperature under argon for 18 hours. Theresulting mixture was diluted with dichloromethane and washed withsaturated sodium bicarbonate solution and brine. The organic layer wasdried under magnesium sulphate and evaporated in vacuo to give the titlecompound. MS (ES+) m/e 317 [M+H]⁺

Step 4: 1,1-Dimethylethyl4-(2-fluoro-4-{[1-(1-methylethyl)-4-piperidinyl]oxy}phenyl)-1-piperazinecarboxylate

The title compound was prepared from the product of step 3 and1,1-dimethylethyl 1-piperazinecarboxylate using the method of Example305 Step 3. MS (ES+) m/e 422 [M+H]⁺

Step 5:1-(2-Fluoro-4-{[1-(1-methylethyl)-4-piperidinyl]oxy}phenyl)piperazine

The title compound was prepared from the product of step 4 using theprocedure of Example 295 Step 5. MS (ES+) m/e 322 [M+H]⁺

Step 6:4-{[4-(2-Fluoro-4-{[1-(1-methylethyl)-4-piperidinyl]oxy}phenyl)-1-piperazinyl]carbonyl}morpholine

The title compound was prepared from the product step 5 and morpholinecarbonyl chloride using the procedure of Example 314. MS (ES+) m/e 435[M+H]⁺

EXAMPLE 3164-{[(2R,6S)-2,6-Dimethyl-4-(4-{[3-(1-piperidinyl)propyl]oxy}phenyl)-1-piperazinyl]carbonyl}benzonitrile(E316)

Step 1: 1-{3-[(4-Iodophenyl)oxy]propyl}piperidine

1-(3-Chloropropyl)piperidine hydrochloride (9.9 g, 50.0 mmol), potassiumcarbonate (17.6 g, 127.4 mmol) and potassium iodide (1.1 g, 6.8 mmol)were added to a solution of 4-iodophenol (10 g, 45.5 mmol) indimethylformamide (150 ml) and the resulting mixture was heated at 90°C. for 18 hours. The mixture was allowed to cool to ambient temperature,poured onto water/ice (500 ml) and stirred for 10 minutes. The solid wasfiltered and washed with ice water to give the title compound (13.5 g).MS (ES+) m/e 346 [M+H]⁺

Step 2:(3R,5S)-3,5-Dimethyl-1-(4-{[3-(1-piperidinyl)propyl]oxy}phenyl)piperazine

The title compound was prepared from the product of step 1 and(2R,6S)-2,6-dimethylpiperazine using the procedure of Example 305 Step3. MS (ES+) m/e 332 [M+H]⁺

Step 3:4-{[(2R,6S)-2,6-Dimethyl-4-(4-{[3-(1-piperidinyl)propyl]oxy}phenyl)-1-piperazinyl]carbonyl}benzonitrile

The product from step 2 (249 mg, 0.75 mmol) was dissolved in drydichloromethane (5 ml), treated with triethylamine (0.21 ml, 1.50 mmol)and 4-cyanobenzoyl chloride (248 mg, 1.50 mmol) and the resultingmixture was stirred at ambient temperature under argon for 2 hours.Methanol was added and the mixture passed down an SCX ion exchangecolumn (5 g) eluting with methanol followed by a mixture of 0.880ammonia:methanol (1:9). The basic fractions were combined and evaporatedin vacuo. The residue was purified by silica gel chromatography elutingwith ammonia:methanol:dichloromethane (0.5:4.5:95) to give the titlecompound (158 mg). MS (ES+) m/e 461 [M+H]⁺

EXAMPLE 317(2R,6S)-2,6-Dimethyl-4-(4-{[3-(1-piperidinyl)propyl]oxy}phenyl)-1-(4-pyridinylcarbonyl)piperazine(E317)

4-Pyridinecarboxylic acid (116 mg, 0.94 mmol) was dissolved in drydichloromethane (5 ml), treated with oxalyl chloride (0.08 ml, 0.96mmol) and dimethylformamide (1 drop) and stirred under argon at ambienttemperature for 2 hours. The solvent was removed in vacuo and theresidue azeotroped with toluene. The residue was redissolved in drydichloromethane (5 ml) and treated with the product from Example 316Step 2 (156 mg, 0.47 mmol) and triethylamine (0.13 ml, 0.94 mmol). Theresulting mixture was stirred under argon at ambient temperature for 1.5hours, diluted with methanol and passed down an SCX ion exchange column(5 g) eluting with methanol followed by a mixture of 0.880ammonia:methanol (1:9). The basic fractions were combined and evaporatedin vacuo. The residue was purified by silica gel chromatography elutingwith ammonia:methanol:dichloromethane (0.7:6.3:93) to give the titlecompound (110 mg). MS (ES+) m/e 437 [M+H]⁺

EXAMPLE 3184-{[(2S)-2-Methyl-4-(4-{[3-(1-piperidinyl)propyl]oxy}phenyl)-1-piperazinyl]carbonyl}benzonitrile(E318)

Step 1:(3S)-3-Methyl-1-(4-{[3-(1-piperidinyl)propyl]oxy}phenyl)piperazine

The title compound was prepared from the product of Example 316 Step 1and (2S)-2-methylpiperazine using the procedure of Example 305 Step 3.MS (ES+) m/e 318 [M+H]⁺

Step 2:4-{[(2S)-2-Methyl-4-(4-{[3-(1-piperidinyl)propyl]oxy}phenyl)-1-piperazinyl]carbonyl}benzonitrile

The title compound was prepared from the product of step 1 and4-cyanobenzoic acid using the procedure of Example 305 Step 5. MS (ES+)m/e 447 [M+H]⁺

EXAMPLES 319-324

The following compounds were prepared from the product of Example 318Step 1 with the appropriate carboxylic acid indicated in the table belowusing the procedure of Example 305 Step 5.

MS (ES+) m/e Example Carboxylic Acid [M + H]⁺(2S)-2-Methyl-4-(4-{[3-(1-piperidinyl)propyl]oxy}phenyl)- 4-(1- 5191-{[4-(1-pyrrolidinylcarbonyl)phenyl]carbonyl}piperazinepyrrolidinylcarbonyl)benzoic (E319) acid (J. Med. Chem., 46(10),1845-1857, 2003)(2S)-2-Methyl-4-(4-{[3-(1-piperidinyl)propyl]oxy}phenyl)-4-pyridinecarboxylic 423 1-(4-pyridinylcarbonyl)piperazine acid (E320)(2S)-1-[(4-Fluorophenyl)carbonyl]-2-methyl-4- 4-fluorobenzoic acid 440(4-{[3-(1-piperidinyl)propyl]oxy}phenyl)piperazine (E321)(2S)-2-Methyl-4-(4-{[3-(1- tetrahydro-2H- 430piperidinyl)propyl]oxy}phenyl)-1-(tetrahydro- pyran-4-carboxylic2H-pyran-4-ylcarbonyl)piperazine (E322) acid(2S)-2-Methyl-1-{[4-(methylsulfonyl)phenyl]carbonyl}-4-(methylsulfonyl)benzoic 5004-(4-{[3-(1-piperidinyl)propyl]oxy}phenyl)piperazine acid (E323)1-(4-{[(2S)-2-Methyl-4-(4-{[3-(1- 4-acetylbenzoic acid 464piperidinyl)propyl]oxy}phenyl)-1- piperazinyl]carbonyl}phenyl)ethanone(E324)

EXAMPLE 3254-{[(3R)-3-Methyl-4-(4-{[3-(1-piperidinyl)propyl]oxy}phenyl)-1-piperazinyl]carbonyl}benzonitrile(E325)

Step 1: 1,1-Dimethylethyl(3R)-3-methyl-4-(4-{[3-(1-piperidinyl)propyl]oxy}phenyl)-1-piperazinecarboxylate

The title compound was prepared from the product of Example 316 Step 1and 1,1-dimethylethyl (3R)-3-methyl-1-piperazinecarboxylate using themethod of Example 305 Step 3. MS (ES+) m/e 418 [M+H]⁺

Step 2:(2R)-2-Methyl-1-(4-{[3-(1-piperidinyl)propyl]oxy}phenyl)piperazine

The title compound was prepared from the product of step 1 using themethod of Example 295 Step 5. MS (ES+) m/e 318 [M+H]⁺

Step 3:4-{[(3R)-3-Methyl-4-(4-{[3-(1-piperidinyl)propyl]oxy}phenyl)-1-piperazinyl]carbonyl}benzonitrile

The title compound was prepared from the product of step 2 and4-cyanobenzoic acid using the procedure of Example 305 Step 5. MS (ES+)m/e 447 [M+H]⁺

EXAMPLES 326-329

The following compounds were prepared from the product of Example 325Step 2 with the appropriate carboxylic acid indicated in the table belowusing the procedure of Example 305 Step 5.

MS (ES+) m/e Example Carboxylic Acid [M + H]⁺ (2R)-2-Methyl-1-(4-{[3-(1-4-(1-pyrrolidinyl 519 piperidinyl)propyl]oxy}phenyl)-4-{[4-(1-carbonyl)benzoic pyrrolidinylcarbonyl)phenyl]carbonyl}piperazine acid(E326) (J. Med. Chem., 46(10), 1845-1857, 2003)(2R)-2-Methyl-1-(4-{[3-(1- 4-pyridine 423piperidinyl)propyl]oxy}phenyl)-4-(4- carboxylic acidpyridinylcarbonyl)piperazine (E327)(2R)-4-[(4-Fluorophenyl)carbonyl]-2-methyl-1-(4-{[3- 4-fluorobenzoic 440(1-piperidinyl)propyl]oxy}phenyl)piperazine (E328) acid(2R)-2-Methyl-1-(4-{[3-(1- tetrahydro-2H- 430piperidinyl)propyl]oxy}phenyl)-4-(tetrahydro-2H- pyran-4-pyran-4-ylcarbonyl)piperazine (E329) carboxylic acid

EXAMPLE 3301-(4-{[3-(1-Piperidinyl)propyl]oxy}phenyl)-4-{[4-(trifluoromethyl)phenyl]carbonyl}piperazine(E330)

4-(Trifluoromethyl)phenyl [4-(trifluoromethyl)phenyl]carbonyl carbonate(358 mg, 1 mmol) was added to a stirring solution of1-(4-{[3-(1-piperidinyl)propyl]oxy}phenyl)piperazine (D11) (150 mg, 0.5mmol) in dichloromethane (20 ml). After 3 hours the mixture was passedthrough an SCX ion exchange cartridge eluting with methanol and then amixture of 0.880 ammonia:methanol (1:9). The basic fractions wereevaporated and the residue purified on silica gel eluting with a mixtureof 0.88 ammonia solution:methanol:dichloromethane (0.5:4.5:95) tofurnish the title compound (204 mg, 87%) MS (ES+) m/e 476 [M+H]⁺.

EXAMPLE 3311-(Cyclohexylcarbonyl)-4-(4-{[3-(1-piperidinyl)propyl]oxy}phenyl)piperazine(E331)

Cyclohexanecarbonyl chloride (79 mg, 0.55 mmol) was added to a mixtureof 1-(4-{[3-(1-piperidinyl)propyl]oxy}phenyl)piperazine (D11) (150 mg,0.5 mmol) and triethylamine (100 μl, 0.75 mmol) in dichloromethane (5ml). After 5 hours the solvent was removed by evaporation and theresidue purified on silica gel eluting with a mixture of 0.88 ammoniasolution:methanol:dichloromethane (0.5:4.5:95) to furnish the titlecompound (150 mg, 89%)

MS (ES+) m/e 414 [M+H]⁺.

EXAMPLES 332-342

E332 to E342 were prepared from1-(4-{[3-(1-piperidinyl)propyl]oxy}phenyl)piperazine (D11) with theappropriate acid chloride indicated in the table below using theprocedure of Example 331

MS (ES+) m/e Compound Acid Chloride [M + H]⁺.1-(4-{[3-(1-Piperidinyl)propyl]oxy}phenyl)-4-(2- 2-thiophene 414thienylcarbonyl)piperazine (E332) carbonyl chloride3-{[4-(4-{[3-(1-Piperidinyl)propyl]oxy}phenyl)-1- 4-cyanobenzoyl 433piperazinyl]carbonyl}benzonitrile (E333) chloride1-{[4-(Methyloxy)phenyl]carbonyl}-4-(4-{[3-(1- 4-(methyloxy)benzoyl 438piperidinyl)propyl]oxy}phenyl)piperazine (E334) chloride1-(1,3-Benzodioxol-5-ylcarbonyl)-4-(4-{[3-(1- 1,3- 452piperidinyl)propyl]oxy}phenyl)piperazine (E335) benzodioxole-5- carbonylchloride 1-{[3,5-bis(Trifluoromethyl)phenyl]carbonyl}-4-(4-3,5-bis(trifluoromethyl)benzoyl 544{[3-(1-piperidinyl)propyl]oxy}phenyl)piperazine chloride (E336)1-[(3,5-Dichlorophenyl)carbonyl]-4-(4-{[3-(1- 3,5- 477piperidinyl)propyl]oxy}phenyl)piperazine (E337) dichlorobenzoyl chloride1-[(4-Bromophenyl)carbonyl]-4-(4-{[3-(1- 4-bromobenzoyl 486piperidinyl)propyl]oxy}phenyl)piperazine (E338) chloride1-[(3-Bromophenyl)carbonyl]-4-(4-{[3-(1- 3-bromobenzoyl 486piperidinyl)propyl]oxy}phenyl)piperazine (E339) chloride1-[(2,6-Dichlorophenyl)carbonyl]-4-(4-{[3-(1- 2,6- 477piperidinyl)propyl]oxy}phenyl)piperazine (E340) dichlorobenzoyl chloride1-(2-Naphthalenylcarbonyl)-4-(4-{[3-(1- 2-naphthalene 458piperidinyl)propyl]oxy}phenyl)piperazine (E341) carbonyl chloride1-(4-{[3-(1-Piperidinyl)propyl]oxy}phenyl)-4-(3- 3-pyridine 409pyridinylcarbonyl)piperazine (E342) carbonyl chloride

EXAMPLE 3431-[(4-Chlorophenyl)carbonyl]-4-(4-{[3-(1-piperidinyl)propyl]oxy}phenyl)piperazine(E343)

4-Chlorobenzoic acid (192 mg, 1.23 mmol) was treated withN,N′-dicyclohexylcarbodiimide (0.25 g, 1.23 mmol) and1-hydroxybenzotriazole hydrate (165 mg, 1.23 mmol) in dichloromethane (5ml) after 2 hours 1-(4-{[3-(1-piperidinyl)propyl]oxy}phenyl)piperazine(D11) (150 mg, 0.5 mmol) was added and stirring continued for 18 hours.The solvent was removed by evaporation and the residue purified onsilica gel eluting with a mixture of 0.88 ammoniasolution:methanol:dichloromethane (0.5:4.5:95) to furnish the titlecompound (198 mg, 91%) MS (ES+) m/e 442 [M+H]⁺.

EXAMPLES 344-374

E344 to E374 were prepared from1-(4-{[3-(1-piperidinyl)propyl]oxy}phenyl)piperazine (D11) with theappropriate carboxylic acid indicated in the table below using theprocedure of Example 343.

MS (ES+) m/e Compound Acid [M + H]⁺.1-[(4-Fluorophenyl)carbonyl]-4-(4-{[3-(1- 4-Fluorobenzoic 426piperidinyl)propyl]oxy}phenyl)piperazine (E344) acid1-(4-Biphenylylcarbonyl)-4-(4-{[3-(1- 4-biphenyl 484piperidinyl)propyl]oxy}phenyl)piperazine (E345) carboxylic acid1-(4-{[3-(1-Piperidinyl)propyl]oxy}phenyl)-4- tetrahydro-2H- 416(tetrahydro-2H-pyran-4-ylcarbonyl)piperazine pyran-4- (E346) carboxylicacid 1-(4-{[3-(1-Piperidinyl)propyl]oxy}phenyl)-4-(2- 2-pyridine 409pyridinylcarbonyl)piperazine (E347) carboxylic acid1-{[4-(4-{[3-(1-Piperidinyl)propyl]oxy}phenyl)-1- 1-isoquinoline 459piperazinyl]carbonyl}isoquinoline (E348) carboxylic acid2-{[4-(4-{[3-(1-Piperidinyl)propyl]oxy}phenyl)-1- 2-quinoline 459piperazinyl]carbonyl}quinoline (E349) carboxylic acid6-{[4-(4-{[3-(1-Piperidinyl)propyl]oxy}phenyl)-1- 6-quinoline 459piperazinyl]carbonyl}quinoline (E350) carboxylic acid1-(4-{[3-(1-Piperidinyl)propyl]oxy}phenyl)-4-(4- 4-pyridine 409pyridinylcarbonyl)piperazine (E351) carboxylic acid5-{[4-(4-{[3-(1-Piperidinyl)propyl]oxy}phenyl)-1- 5-pyrimidine 410piperazinyl]carbonyl}pyrimidine (E352) carboxylic acid1-(4-{[3-(1-Piperidinyl)propyl]oxy}phenyl)-4-(3- 3-thiophene 414thienylcarbonyl)piperazine (E353) carboxylic acid Methyl4-{[4-(4-{[3-(1- 4-[(methyloxy)carbonyl] 466piperidinyl)propyl]oxy}phenyl)-1- benzoic piperazinyl]carbonyl}benzoate(E354) acid Methyl 3-{[4-(4-{[3-(1- 3-[(methyloxy)carbonyl] 466piperidinyl)propyl]oxy}phenyl)-1- benzoic piperazinyl]carbonyl}benzoate(E355) acid 1-(Cyclopropylacetyl)-4-(4-{[3-(1- cyclopropyl acetic 386piperidinyl)propyl]oxy}phenyl)piperazine (E356) acid1-{[4-Fluoro-2-(trifluoromethyl)phenyl]carbonyl}-4- 4-fluoro-2- 494(4-{[3-(1-piperidinyl)propyl]oxy}phenyl)piperazine(trifluoromethyl)benzoic (E357) acid1-[(4-Bromo-2-methylphenyl)carbonyl]-4-(4-{[3-(1- 4-bromo-2- 501piperidinyl)propyl]oxy}phenyl)piperazine (E358) methylbenzoic acid1-[(4-Chloro-3-fluorophenyl)carbonyl]-4-(4-{[3-(1- 4-chloro-3- 460piperidinyl)propyl]oxy}phenyl)piperazine (E359) fluorobenzoic acid1-{[4-(Methylsulfonyl)phenyl]carbonyl}-4-(4-{[3-(1-4-(methylsulfonyl)benzoic 486 piperidinyl)propyl]oxy}phenyl)piperazine(E360) acid 1-{[2-Chloro-4-(methylsulfonyl)phenyl]carbonyl}-4-2-chloro-4- 521 (4-{[3-(1-piperidinyl)propyl]oxy}phenyl)piperazine(methylsulfonyl)benzoic (E361) acid1-[(2,4-Difluorophenyl)carbonyl]-4-(4-{[3-(1- 2,4-difluoro 444piperidinyl)propyl]oxy}phenyl)piperazine (E362) benzoic acid1-(3-Methylbutanoyl)-4-(4-{[3-(1- 3-methyl butanoic 388piperidinyl)propyl]oxy}phenyl)piperazine (E363) acid1-[(2,4-Dichlorophenyl)carbonyl]-4-(4-{[3-(1- 2,4-dichloro 477piperidinyl)propyl]oxy}phenyl)piperazine (E364) benzoic acid1-[(4-Chloro-2-fluorophenyl)carbonyl]-4-(4-{[3-(1- 4-chloro-2- 461piperidinyl)propyl]oxy}phenyl)piperazine (E365) fluorobenzoic acid1-[(4-Fluoro-3-methylphenyl)carbonyl]-4-(4-{[3-(1- 4-fluoro-3- 440piperidinyl)propyl]oxy}phenyl)piperazine (E366) methylbenzoic acid1-[(4-Bromo-2-fluorophenyl)carbonyl]-4-(4-{[3-(1- 4-bromo-2- 505piperidinyl)propyl]oxy}phenyl)piperazine (E367) fluorobenzoic acid1-[(3,4-Difluorophenyl)carbonyl]-4-(4-{[3-(1- 3,4-difluoro 444piperidinyl)propyl]oxy}phenyl)piperazine (E368) benzoic acid1-[(4-Chloro-3-methylphenyl)carbonyl]-4-(4-{[3-(1- 4-chloro-3- 457piperidinyl)propyl]oxy}phenyl)piperazine (E369) methylbenzoic acid1-[(4-Bromo-3-methylphenyl)carbonyl]-4-(4-{[3-(1- 4-bromo-3- 501piperidinyl)propyl]oxy}phenyl)piperazine (E370) methylbenzoic acid1-[(2-Bromo-4-fluorophenyl)carbonyl]-4-(4-{[3-(1- 2-bromo-4- 505piperidinyl)propyl]oxy}phenyl)piperazine (E371) fluorobenzoic acidN,N-Dimethyl-3-{[4-(4-{[3-(1- 3-(dimethyl 451piperidinyl)propyl]oxy}phenyl)-1- amino)benzoicpiperazinyl]carbonyl}aniline (E372) acid N,N-Dimethyl-4-{[4-(4-{[3-(1-4-(dimethyl 451 piperidinyl)propyl]oxy}phenyl)-1- amino)benzoicpiperazinyl]carbonyl}aniline (E373) acid1-(4-{[3-(1-Piperidinyl)propyl]oxy}phenyl)-4-{[4-(1- 4-(1-pyrrolidinyl505 pyrrolidinylcarbonyl)phenyl]carbonyl}piperazine carbonyl)benzoic(E374) acid (Journal of Medicinal Chemistry (2003), 46(10), 1845-1857)

EXAMPLE 3758-{[4-(4-{[3-(1-Piperidinyl)propyl]oxy}phenyl)-1-piperazinyl]carbonyl}quinoline(E375)

A mixture of 8-quinolinecarboxylic acid (U.S. Pat. Appl. Publ.,20020045225, 18 Apr. 2002) (173 mg, 1 mmol), polymer boundN-cyclohexylcarbodiimide, N-methyl polystyrene HL (200-400 mesh) (526 mgof 1.9 mmol/g resin) and 1-hydroxybenzotriazole hydrate (135 mg, 1 mmol)in dichloromethane (5 ml) was stirred at room temperature for 30minutes. 1-(4-{[3-(1-Piperidinyl)propyl]oxy}phenyl)piperazine (D11) (150mg, 0.5 mmol) was added and stirring continued for 18 hours. The solventwas removed by evaporation and the residue purified on silica geleluting with a mixture of 0.88 ammonia solution:methanol:dichloromethane(0.5:4.5:95) to furnish the title compound (93 mg, 41%) MS (ES+) m/e 459[M+H]⁺.

EXAMPLES 376-431

E376 to E431 were prepared from1-(4-{[3-(1-piperidinyl)propyl]oxy}phenyl)piperazine (D11) with theappropriate carboxylic acid indicated in the table below using theprocedure of Example 375.

MS (ES+) m/e Compound Acid [M + H]⁺.1-(4-{[3-(1-Piperidinyl)propyl]oxy}phenyl)- 3-pyridinylacetic acid 4234-(3-pyridinylacetyl)piperazine (E377)6-Methyl-4-{[4-(4-{[3-(1-piperidinyl)propyl]oxy}phenyl)-6-methyl-2-oxo-1,2-dihydro-4- 439 1-piperazinyl]carbonyl}-pyridinecarboxylic acid 2(1H)-pyridinone (E378)1-(4-{[3-(1-Piperidinyl)propyl]oxy}phenyl)- 2H-tetrazol-2-ylacetic acid414 4-(1H-tetrazol-1- ylacetyl)piperazine (E379)1-(4-{[3-(1-Piperidinyl)propyl]oxy}phenyl)- 4-(1H-pyrrol-1-yl)benzoicacid 473 4-{[4-(1H-pyrrol-1- yl)phenyl]carbonyl}piperazine (E380)1-Acetyl-4-(4-{[3-(1-piperidinyl)propyl]oxy}phenyl)piperazine Aceticacid 346 (E381) 1-(4-{[3-(1-Piperidinyl)propyl]oxy}phenyl)-4-(1H-1,2,3-triazol-1- 413 4-(1H-1,2,3-triazol-1- yl)benzoic acidylacetyl)piperazine (E382)1-{2-Oxo-2-[4-(4-{[3-(1-piperidinyl)propyl]oxy}phenyl)-(2-oxo-1(2H)-pyridinyl)acetic 439 1-piperazinyl]ethyl}- acid(Tetrahedron Letters 2(1H)-pyridinone (E383) (1998), 39(34), 6167-6170)6-{[4-(4-{[3-(1-Piperidinyl)propyl]oxy}phenyl)- 6-quinoxalinecarboxylicacid 460 1-piperazinyl]carbonyl}quinoxaline (E384)5-{[4-(4-{[3-(1-Piperidinyl)propyl]oxy}phenyl)- 5-quinoxalinecarboxylicacid 460 1-piperazinyl]carbonyl}quinoxaline (E385)1-(4-{[4-(4-{[3-(1-Piperidinyl)propyl]oxy}phenyl)- 4-acetylbenzoic acid450 1-piperazinyl]carbonyl}phenyl)ethanone (E386)1-[(Methylsulfonyl)acetyl]-4-(4-{[3-(1- (methylsulfonyl)acetic acid 424piperidinyl)propyl]oxy}phenyl)piperazine (E387)1-(4-{[3-(1-Piperidinyl)propyl]oxy}phenyl)- 1,3-thiazole-5-carboxylicacid 415 4-(1,3-thiazol-5- (Izvestiya Akademii Naukylcarbonyl)piperazine (E388) SSSR, Seriya Khimicheskaya, (1), 132-6;1976) 1-(5-Isothiazolylacetyl)-4-(4-{[3-(1- 5-isothiazolylacetic acid429 piperidinyl)propyl]oxy}phenyl)piperazine (Journal of Medicinal(E389) Chemistry (1967), 11(1), 70-3.)3-{[4-(4-{[3-(1-Piperidinyl)propyl]oxy}phenyl)- 1,2-benzisoxazole-3- 4491-piperazinyl]carbonyl}-1,2- carboxylic acid benzisoxazole (E390)1-(4-{[3-(1-Piperidinyl)propyl]oxy}phenyl)-3-(1-pyrrolidinylcarbonyl)benzoic 5054-{[3-(1-pyrrolidinylcarbonyl)phenyl]carbonyl}piperazine acid (WO0304468) (E391) 2-{[4-(4-{[3-(1-Piperidinyl)propyl]oxy}phenyl)-2-quinoxalinecarboxylic acid 460 1-piperazinyl]carbonyl}quinoxaline(Organic Process Research & (E392) Development, 6(4), 477-481; 2002)4-{[4-(4-{[3-(1-Piperidinyl)propyl]oxy}phenyl)- 4-quinolinecarboxylicacid 459 1-piperazinyl]carbonyl}quinoline (E393)4-{[4-(4-{[3-(1-Piperidinyl)propyl]oxy}phenyl)-6-cyano-3-pyridinecarboxylic 434 1-piperazinyl]carbonyl}cinnoline acid(J. Am. Chem. Soc., 68, (E394) 1310-13; 1946) 3-{[4-(4-{[3-(1-pyrazolo[1,5-a]pyrazine-3- 449 Piperidinyl)propyl]oxy}phenyl)-1-carboxylic acid piperazinyl]carbonyl}pyrazolo[1,5- a]pyrimidine (E395)1-[(2-Chloro-6-methyl-4-pyridinyl)carbonyl]- 2-chloro-6-methyl-4- 4584-(4-{[3-(1-piperidinyl)propyl]oxy}phenyl)piperazine pyridinecarboxylicacid (E396) 1-[(1-Methyl-1H-1,2,3-triazol-4-1-methyl-1H-1,2,3-triazole-4- 413yl)carbonyl]-4-(4-{[3-(1-piperidinyl)propyl]oxy}phenyl)piperazinecarboxylic acid (E397) (Journal of Organic Chemistry (1976), 41(6),1041-51) 2-{[4-(4-{[3-(1-Piperidinyl)propyl]oxy}phenyl)-1,8-naphthyridine-2- 460 1-piperazinyl]carbonyl}- carboxylic acid1,8-naphthyridine (E398) 5-{[4-(4-{[3-(1-Piperidinyl)propyl]oxy}phenyl)-1H-indole-5-carboxylic acid 447 1-piperazinyl]carbonyl}-1H- indole(E399) 2-{[4-(4-{[3-(1-Piperidinyl)propyl]oxy}phenyl)-4-pyrimidinecarboxylic acid 410 1-piperazinyl]carbonyl}pyrazine (E400)3-{[4-(4-{[3-(1-Piperidinyl)propyl]oxy}phenyl)-pyrazolo[1,5-a]pyridine-3- 448 1-piperazinyl]carbonyl}pyrazolo[1,carboxylic acid 5-a]pyridine (E401)1-(4-{[3-(1-Piperidinyl)propyl]oxy}phenyl)- 4-(1H-tetrazol-1-yl)benzoic476 4-{[4-(1H-tetrazol-1- acid yl)phenyl]carbonyl}piperazine (E402)1-(1-Benzofuran-2-ylcarbonyl)-4-(4-{[3- Benzofuran-2-carboxylic acid 448(1-piperidinyl)propyl]oxy}phenyl)piperazine (E403)1-(3-Isoxazolylcarbonyl)-4-(4-{[3-(1- 3-Isoxazolecarboxylic acid 399piperidinyl)propyl]oxy}phenyl)piperazine (E404)5-{[4-(4-{[3-(1-Piperidinyl)propyl]oxy}phenyl)- 2,1,3-Benzoxo-diazole-5-450 1-piperazinyl]carbonyl}-2,1,3- carboxylic acid benzoxadiazole (E405)1-(4-{[3-(1-Piperidinyl)propyl]oxy}phenyl)- 3-Thiopheneacetic acid 4284-(3-thienylacetyl)piperazine (E406)1-(4-{[3-(1-Piperidinyl)propyl]oxy}phenyl)- 1,2,3-Thiadiazole-4- 4164-(1,2,3-thiadiazol-4- carboxylic acid ylcarbonyl)piperazine (E407)4-{2-Oxo-2-[4-(4-{[3-(1- 4-Cyanobenzeneacetic acid 447piperidinyl)propyl]oxy}phenyl)-1- (WO 0247762)piperazinyl]ethyl}benzonitrile (E408) 1-(2,3-Dihydro-1-benzofuran-7-2,3-Dihydrobenzofuran-7- 450ylcarbonyl)-4-(4-{[3-(1-piperidinyl)propyl]oxy}phenyl)piperazinecarboxylic acid (E409) 1-[(1,1-Dioxidotetrahydro-2H-thiopyran-1,1-dioxohexahydro-1lambda 4644-yl)carbonyl]-4-(4-{[3-(1-piperidinyl)propyl]oxy}phenyl)piperazine6-thiopyran-4-carboxylic acid (E410)1-(4-{2-Oxo-2-[4-(4-{[3-(1-piperidinyl)propyl]oxy}phenyl)-4-Acetylphenylacetic acid 464 1-piperazinyl]ethyl}phenyl)ethanone(Chemical Communications, (E411) 2001, (20), 2147-2148)1-{[3,5-bis(Methyloxy)phenyl]carbonyl}- 3,5-Dimethoxybenzoic acid 4684-(4-{[3-(1-piperidinyl)propyl]oxy}phenyl)piperazine (E412)1-(2-Methyl-2-phenylpropanoyl)-4-(4- 2-Methyl-2-phenylpropionic 450{[3-(1-piperidinyl)propyl]oxy}phenyl)piperazine acid (E413)1-[(4-Methyl-1,2,3-thiadiazol-5- 4-Methyl-1,2,3-thiadiazole-5- 430yl)carbonyl]-4-(4-{[3-(1-piperidinyl)propyl]oxy}phenyl)piperazinecarboxylic acid (E414)1-(5-{[4-(4-{[3-(1-Piperidinyl)propyl]oxy}phenyl)- 5-Acetylthiophene-2-456 1-piperazinyl]carbonyl}-2- carboxylic acid thienyl)ethanone (E415)4-{3-Oxo-3-[4-(4-{[3-(1- 4-Cyanobenzenepropionic 461piperidinyl)propyl]oxy}phenyl)-1- acid piperazinyl]propyl}benzonitrile(E416) (U.S. Pat. No. 5,726,159)3-{[4-(4-{[3-(1-Piperidinyl)propyl]oxy}phenyl)- 1,2-Benzisothiazole-3-465 1-piperazinyl]carbonyl}- carboxylic acid 1,2-benzisothiazole (E417)(4-{[4-(4-{[3-(1-Piperidinyl)propyl]oxy}phenyl)-2-cyanomethyl-thiazole-4- 454 1-piperazinyl]carbonyl}- carboxylic acid(Bioorganic 1,3-thiazol-2-yl)acetonitrile (E418) and Medicinal ChemistryLetters, 12; 4; 2002; 561-566) 3-{2-Oxo-2-[4-(4-{[3-(1-3-Cyanophenylacetic acid 447 piperidinyl)propyl]oxy}phenyl)-1- (WO0351797) piperazinyl]ethyl}benzonitrile (E419)(4-{[4-(4-{[3-(1-Piperidinyl)propyl]oxy}phenyl)- 4-(Cyanomethyl)benzoicacid 447 1-piperazinyl]carbonyl}phenyl)acetonitrile (E420)1-(3,4-Dihydro-2H-chromen-6- 2H-1-Benzopyran-6- 464ylcarbonyl)-4-(4-{[3-(1-piperidinyl)propyl]oxy}phenyl)piperazinecarboxylic acid, 3,4-dihydro- (E421) (Journal of Heterocyclic Chemistry1994 31 (2) 457-79) 6-{[4-(4-{[3-(1-Piperidinyl)propyl]oxy}phenyl)-Benzothiazole-6-carboxylic 465 1-piperazinyl]carbonyl}- acid1,3-benzothiazole (E422)3,5-Difluoro-4-{[4-(4-{[3-(1-piperidinyl)propyl]oxy}phenyl)-4-cyano-2,6-difluoro-benzoic 469 1-piperazinyl]carbonyl}benzonitrileacid (E423) (U.S. Pat. No. 5,914,319)1-(4-{[3-(1-Piperidinyl)propyl]oxy}phenyl)- 2,4,6-Trifluorobenzoic acid462 4-[(2,4,6-trifluorophenyl)carbonyl]piperazine (E424)1-[3-(Methyloxy)propanoyl]-4-(4-{[3-(1- 3-Methoxypropionic acid 390piperidinyl)propyl]oxy}phenyl)piperazine (E425)1-[3-(2-Furanyl)propanoyl]-4-(4-{[3-(1- 3-(2-Furyl)propionic acid 426piperidinyl)propyl]oxy}phenyl)piperazine (E426)1-[(Methyloxy)acetyl]-4-(4-{[3-(1- Methoxyacetic acid 376piperidinyl)propyl]oxy}phenyl)piperazine (E427)1-[(3,5-Dimethyl-1H-1,2,4-triazol-1- (3,5-dimethyl-1H-1,2,4-triazol- 441yl)acetyl]-4-(4-{[3-(1-piperidinyl)propyl]oxy}phenyl)piperazine1-yl)acetic acid (E428) 1-[(3,5-Dimethyl-4-isoxazolyl)carbonyl]-3,5-Dimethylisoxazole-4- 4274-(4-{[3-(1-piperidinyl)propyl]oxy}phenyl)piperazine carboxylic acid(E429) 1-(4-{[3-(1-Piperidinyl)propyl]oxy}phenyl)-Tetrahydrothiopyran-4- 432 4-(tetrahydro-2H-thiopyran-4- carboxylic acidylcarbonyl)piperazine (E430) (Helvetica. Chimica. Acta. 1997 80 (5)1528-1554) 1-[(1-Oxidotetrahydro-2H-thiopyran-4-2H-Thiopyran-4-carboxylic 448yl)carbonyl]-4-(4-{[3-(1-piperidinyl)propyl]oxy}phenyl)piperazine acid,tetrahydro-, 1-oxide (E431) (Arkiv foer Kemi (1966), 26(6), 73-7)

EXAMPLE 432 Methyl4-{[4-(4-{[3-(1-piperidinyl)propyl]oxy}phenyl)-1-piperazinyl]carbonyl}benzoate(E432)

Methyl 4-chlorocarbonylbenzoate (3.6 g, 18.12 mM) was added to asolution of 1-[4-(3-Piperidin-1-yl-propoxy)-phenyl]-piperazine (D11) (5g, 16.48 mM) and triethylamine (2.53 ml, 18.12 mM) in dichloromethane(25 ml), and the resulting solution stirred at room temperature for 16hours. A saturated aqueous solution of sodium bicarbonate (25 ml) wasadded to the reaction and stirred for 1 hour. The organic phase wasseparated, washed with water, dried over anhydrous sodium sulfate andevaporated in vacuo to afford the title compound (7.46 g); MS (ES+) m/e466 [M+H]⁺.

EXAMPLE 4334-{[4-(4-{[3-(1-Piperidinyl)propyl]oxy}phenyl)-1-piperazinyl]carbonyl}benzoicacid (E433)

To a solution of methyl4-{[4-(4-{[3-(1-piperidinyl)propyl]oxy}phenyl)-1-piperazinyl]carbonyl}benzoate(E432) (6.45 g, 13.86 mM) in a mixture of methanol:water (5:1) (90 ml)was added lithium hydroxide (365 mg, 15.24 mM) and the reaction stirredat room temperature for 3 days. Acetic acid (3.17 ml, 55.44 mM) wasadded and the reaction stirred for an additional 10 minutes. The solventwas evaporated in vacuo and the resulting residue dissolved in a mixtureof methanol/dichloromethane (1:10) (20 ml), and purified using silicagel chromatography eluting with a mixture of 0.880ammonia:methanol:dichloromethane (2:18:80) to afford the title compound(6.21 g); MS (ES+), m/e 452 [M+H]⁺.

EXAMPLE 4341-{[4-(1-piperazinylcarbonyl)phenyl]carbonyl}-4-(4-{[3-(1-piperidinyl)propyl]oxy}phenyl)piperazine(E434)

Step 1: 1,1-Dimethylethyl4-[(4-{[4-(4-{[3-(1-piperidinyl)propyl]oxy}phenyl)-1-piperazinyl]carbonyl}phenyl)carbonyl]-1-piperazinecarboxylate

N-Cyclohexylcarbodiimide, N-methyl polystyrene HL (200-400 mesh) 1.9mMol/g (530 mg, 1 mM) was suspended in dichloromethane (10 ml) andtreated sequentially with4-{[4-(4-{[3-(1-piperidinyl)propyl]oxy}phenyl)-1-piperazinyl]carbonyl}benzoicacid (E433) (225 mg, 1 mM), 1-hydroxybenzotriazole hydrate (135 mg, 1mM) and tert-butyl 1-piperazinecarboxylate (93 mg, 0.5 mM) and stirredat room temperature for 16 hours. After filtration, the filtrate wasapplied to a Mega Bond elute SCX ion exchange column washingsequentially with water and methanol, followed by 0.880 ammonia:methanol(1:10) to elute the crude reaction mixture. Purification by silica gelchromatography eluting with a mixture of 0.880ammonia:methanol:dichloromethane (0.5:4.5:95) to afford the titleproduct (162 mg); MS (ES+), m/e 620 [M+H]⁺.

Step 2:1-{[4-(1-piperazinylcarbonyl)phenyl]carbonyl}-4-(4-{[3-(1-piperidinyl)propyl]oxy}phenyl)piperazine

The title compound was prepared from the product of step 1 (162 mg, 0.26mM) using the procedure detailed in description D11; MS (ES+), m/e 520[M+H]⁺

EXAMPLES 435-445

E435 to E445 were prepared from4-{[4-(4-{[3-(1-piperidinyl)propyl]oxy}phenyl)-1-piperazinyl]carbonyl}benzoicacid (E433) with the appropriate amine indicated in the table belowusing the procedure of Example 434 step 1.

MS (ES+) m/e Compound Amine [M + H]⁺.1-{[4-(1-Piperidinylcarbonyl)phenyl]carbonyl}-4-(4- Piperidine 519{[3-(1-piperidinyl)propyl]oxy}phenyl)piperazine (E435)4-[(4-{[4-(4-{[3-(1-Piperidinyl)propyl]oxy}phenyl)-1- Morpholine 521piperazinyl]carbonyl}phenyl)carbonyl]morpholine (E436)4-[(4-{[4-(4-{[3-(1-Piperidinyl)propyl]oxy}phenyl)-1- Thiomorpholine 537piperazinyl]carbonyl}phenyl)carbonyl]thiomorpholine (E437)1-({4-[(4-Methyl-1-piperidinyl)carbonyl]phenyl}carbonyl)- 4-Methyl 5334-(4-{[3-(1-piperidinyl)propyl]oxy}phenyl)piperazine piperidine (E438)N,N-Diethyl-4-{[4-(4-{[3-(1-piperidinyl)propyl]oxy}phenyl)- Diethylamine507 1-piperazinyl]carbonyl}benzamide (E439)N,N-Dimethyl-4-{[4-(4-{[3-(1-piperidinyl)propyl]oxy}phenyl)-Dimethylamine 479 1-piperazinyl]carbonyl}benzamide (E440) 2M Solution inTetrahydrofuranN-Cyclopentyl-4-{[4-(4-{[3-(1-piperidinyl)propyl]oxy}phenyl)-Cyclopentyl 519 1-piperazinyl]carbonyl}benzamide (E441) amine1-{[4-(1-Azetidinylcarbonyl)phenyl]carbonyl}-4-(4- Azetidine 491{[3-(1-piperidinyl)propyl]oxy}phenyl)piperazine (E442)1-[(4-{[(3S)-3-Fluoro-1-pyrrolidinyl]carbonyl}phenyl)carbonyl]-(S)-3-Fluoro 523 4-(4-{[3-(1-piperidinyl)propyl]oxy}phenyl)piperazinepyrrolidine (E443) WO 9108206 1-{[4-({(2R)-2-[(Methyloxy)methyl]-1-(R)-2-(Methoxy 549 pyrrolidinyl}carbonyl)phenyl]carbonyl}-4-(4-{[3-(1-methyl)pyrrolidine piperidinyl)propyl]oxy}phenyl)piperazine (E444)(3R)-1-[(4-{[4-(4-{[3-(1-Piperidinyl)propyl]oxy}phenyl)- (R)-(+)-3- 5211-piperazinyl]carbonyl}phenyl)carbonyl]-3- Pyrrolidinol pyrrolidinol(E445)

EXAMPLE 4461-(3-Fluoro-4-{[3-(1-piperidinyl)propyl]oxy}phenyl)-4-(phenylcarbonyl)piperazine(E446)

Step 1: 1-{3-[(4-Bromo-2-fluorophenyl)oxy]propyl}piperidine

2-Fluoro-4-bromophenol (4.20 g, 22 mmol), 1-(3-chloropropyl)piperidine(3.96 g, 20 mmol), potassium carbonate (8.26 g, 60 mmol) and catalyticpotassium iodide were heated at reflux for 24 hours in 2-butanone (100ml). The solids were filtered, washed with acetone and concentrated invacuo to a crude oil. The residue was purified on silica gel elutingwith a mixture of ethyl acetate:hexane (0.7:0.3) and then ethyl acetate,to afford the title compound (5.71 g, 90%); MS (ES+) m/e 315/317 [M+H]⁺.

Step 2: 1,1-Dimethylethyl4-(3-fluoro-4-{[3-(1-piperidinyl)propyl]oxy}phenyl)-1-piperazinecarboxylate

The product of step 1 (632 mg, 2 mmol), sodium tert-butoxide (538 mg,5.6 mmol), tert-butyl 1-piperazinecarboxylate (894 mg, 4.8 mmol),tris(dibenzylidineacetone)dipalladium(0) (18 mg, 0.01 mmol) andtris(o-tolyl)phosphine (24 mg, 0.08 mmol) were heated at reflux intoluene (10 ml) for 16 hours. The solution was loaded directly on to aSCX ion exchange resin eluting with methanol and then a mixture of 0.88ammonia solution:methanol (1:9). The basic fractions were evaporated andthe residue purified by silica gel chromatography, eluting with amixture of 0.880 ammonia:ethanol:dichloromethane (1:9:190) to afford thetitle compound (468 mg, 54%); MS (ES+) m/e 422 [M+H]⁺.

Step 3: 1-(3-Fluoro-4-{[3-(1-piperidinyl)propyl]oxy}phenyl)piperazine

The product of step 2 (468 mg, 1.1 mmol) was dissolved in 1:1 TFA:DCM(10 ml) at 0° C. and stirred to room temperature over 2 hours. Thesolution was concentrated in vacuo and co-evaporated three times withdichloromethane. The residue was passed through a SCX ion exchange resineluting with methanol and then a mixture of 0.88 ammoniasolution:methanol (1:9). The basic fractions were evaporated and theresidue purified by silica gel chromatography, eluting withdichloromethane then a mixture of 0.880 ammonia:ethanol:dichoromethane(1:9:90) to afford the title compound (320 mg, 90%); MS (ES+) m/e 322[M+H]⁺.

Step 4:1-(3-Fluoro-4-{[3-(1-piperidinyl)propyl]oxy}phenyl)-4-(phenylcarbonyl)piperazine

The product of step 3 (320 mg, 1 mmol) and triethylamine (140 μL, 1mmol) were dissolved in dichloromethane (5 ml), and treated with benzoylchloride (115 μL, 1 mmol) added. The solution was stirred at roomtemperature overnight and concentrated in vacuo to a crude solid. Thesolid was purified by silica gel chromatography eluting withdichloromethane then a mixture of 0.880 ammonia:ethanol:dichoromethane(1:9:90) to afford the title compound (354 mg, 83%); MS (ES+) m/e 426[M+H]⁺.

EXAMPLE 4474-[4-(3-Piperidin-1-yl-propoxy)-naphthalen-1-yl]-piperazine-1-carboxylicacid tert-butyl ester (E447)

Step 1: 4-Bromo-naphthalen-1-ol

1-naphthol (1 g, 6.94 mmol) in acetonitrile (25 ml) was treated withN-bromosuccinimide (1.6 g, 9.01 mmol) and the mixture was stirred atroom temperature for 3 hours. The solvent was removed in vacuo and theresidue was purified by silica gel chromatography eluting with a mixtureof hexane:ethyl acetate (0.9:1) to afford the title compound (0.85 g,57%); MS (ES−) m/e 222 [M−H]⁻.

Step 2: 1-[3-(4-Bromo-naphthalen-1-yl oxy)-propyl]-piperidine

The product from step 1 (0.85 g, 3.83 mMol) in 2-Butanone (30 ml), wastreated with 1-(3-Chloro-propyl)-piperidine (0.74 g, 4.59 mMol),potassium carbonate (1.2 g, 9.19 mMol), followed by potassium iodide(1.5 g, 9.19 mMol) and heated under reflux for 6 hours. After cooling toroom temperature, the reaction mixture was treated with sodiumthiosulphate (1M, 10 ml) the product was extracted into ethyl acetate,washed with water (×3), brine (×1), dried over magnesium sulphate andconcentrated in vacuo. The residue was purified on silica gel elutingwith a mixture of 0.88 ammonia solution:methanol:dichloromethane(0.5:4.5:95) to furnish the title compound (0.88 g, 68%); MS (ES+) m/e350 [M+H]⁺.

Step 3:4-[4-(3-Piperidin-1-yl-propoxy)-naphthalen-1-yl]-piperazine-1-carboxylicacid tert-butyl ester

Palladium bis-tert-butyl phosphine (0.033 g, 0.064 mmol) in ortho-xylene(20 ml) was treated with the product from step 2 (0.45 g, 1.28 mmol),piperazine-1-carboxylic acid tert-butyl ester (1.47 g, 7.67 mMol),followed by sodium tert-butoxide (0.17 g, 1.79 mMol) and heated at 120°C. for 2 hours. After cooling to room temperature the reaction mixturewas diluted with ethyl acetate, washed with water (×3), brine (×1),dried over magnesium sulphate and concentrated in vacuo. The residue waspurified on silica gel eluting with a mixture of 0.88 ammoniasolution:methanol:dichloromethane (0.1:0.9:99) to furnish the titlecompound (0.40 g, 56%); MS (ES+) m/e 454 [M+H]⁺.

EXAMPLE 4484-(1-{4-[4-(3-Piperidin-1-yl-propoxy)-naphthalen-1-yl]-piperazin-1-yl}-methanoyl)-benzonitrile(E448)

Step 1: 1-[4-(3-Piperidin-1-yl-propoxy)-naphthalene-1-yl]-piperazine

A solution of the product from Examples 447, step 3 (0.40 g, 0.89 mmol)in anhydrous dichloromethane (5 ml) was treated with trifluoroaceticacid (10 ml), and stirred at room temperature for 1 hour. The solventwas removed in vacuo, dissolved in methanol and applied to a SCX ionexchange column and eluted with methanol and then a mixture ofmethanol:0.880 ammonia (9:1). The basic fractions were then reduced andthe residue was purified on silica gel eluting with a mixture of 0.88ammonia solution:methanol:dichloromethane (1:9:90) to furnish the titlecompound (0.23 g, 73%); MS (ES+) m/e 354 [M+H]⁺.

Step 2:4-(1-{4-[4-(3-Piperidin-1-yl-propoxy)-naphthalen-1-yl]-piperazin-1-yl}-methanoyl)-benzonitrile

The title compound was prepared from the product of Step 1 (0.13 g, 0.37mmol) and 4-cyanobenzoic acid (0.11 g, 0.74 mmol) according theprocedure detailed in Example 375 (0.17 g, 99%); MS (ES+) m/e 483[M+H]⁺.

EXAMPLE 4491-Phenyl-1-{4-[4-(3-piperidin-1-yl-propoxy)-phenyl-[1,4]diazepan-1-yl}-methanone(E449)

Step 1:4-[4-(3-Piperidin-1-yl-propoxy)-phenyl]-[1,4]diazepane-1-carboxylic acidtert butyl ester

A mixture of the product from Example 316, step 1(1-[3-(4-Iodo-phenoxy)-propyl]-piperidine) (2 g, 5.8 mMol), [1,4]Diazepane-1-carboxylic acid tert butyl ester (2.7 g. 13.9 mMol),tris(dibenzylidenacetone) dipalladium(0) (0.03 g, 0.03 mMol),tri-ortho-tolyl-phosphane (0.04 g, 0.02 mMol) in dioxane (20 ml) washeated at reflux for 20 hours. After cooling to room temperature thereaction mixture was diluted with ethyl acetate, washed with water (×3),brine (×1), dried over magnesium sulphate and concentrated in vacuo. Theresidue was purified by column chromatography eluting with a mixture of0.88 ammonia solution:methanol:dichloromethane (0.1:0.9:99) to furnishthe title compound (0.61 g, 25%);

MS (ES+) m/e 418 [M+H]⁺.

Step 2: 1-[4-(3-Piperidin-1-yl-propoxy)-phenyl]-[1,4]diazepane

The title compound was prepared from the product of step 1 (162 mg, 0.26mM) using the procedure detailed in description D11; MS (ES+) m/e 318[M+H]⁺.

Step 3:1-Phenyl-1-{4-[4-(3-piperidin-1-yl-propoxy)-phenyl-[1,4]diazepan-1-yl}-methanone

The title compound was prepared from the product of step 2 (0.09 g, 0.29mmol) and benzoic acid (0.71 g, 0.58 mmol) using the procedure detailedin Example 375 (0.12 g, 95%); MS (ES+) m/e 422 [M+H]⁺.

EXAMPLES 450-453

E450 to E453 were prepared from Example 449 step 2 with the appropriatecarboxylic acids indicated in the table below using the proceduredetailed in Example 375.

Carboxylic MS (ES+) m/e Compound Acid [M + H]⁺.3-(1-{4-[4-(3-Piperidin-1-yl-propoxy)-phenyl]-[1,4]diazepan- 3-Cyano-447 1-yl}-methanoyl)-benzonitrile (E450) benzoic acid1-Cyclopropyl-1-{4-[4-(3-piperidin-1-yl-propoxy)- Cyclopropane 386phenyl]-[1,4]-diazepan-1-yl}-methanone (E451) carboxylic acid1-(4-Fluoro-phenyl)-1-{4-[4-(3-piperidin-yl-propoxy)- 4-Fluoro- 440phenyl]-[1,4]-diazepan-1-yl}-methanone (E452) benzoic acid1-{4-[4-(3-Piperidin-1-yl-propoxy)-phenyl]-[1,4]diazepan- Thiophene-2-428 1-yl}-1-thiopheny-2-yl-methanone (E453) carboxylic acid

EXAMPLE 4544-(1-{(2S,5R)-2,5-Dimethyl-4-[4-(3-piperidin-1-yl-propoxy)-phenyl]-piperazin-1-yl}-methanoyl)-benzonitrile(E454)

Step 1:(2R,5S)-2,5-Dimethyl-1-[4-(3-piperidin-1-yl-propoxy)-phenyl]-piperazine

A mixture of 2,2′-Bis(diphenylphosphino)-1,′-binaphthyl (0.068 g, 0.109mmol) and palladium acetate (0.016 g, 0.072 mmol) in toluene (5 ml) wereheated to 80° C. To this was added the product from example 316, step 1(1-[3-(4-iodo-phenoxy)-propyl]-piperidine) (0.5 g, 1.45 mmol)pre-dissolved in toluene (5 ml), (2S,5R)-2,5-dimethyl-piperazine (0.20 g1.74 mmol) predissolved in toluene (5 ml), followed by sodiumtert-butoxide (0.20 g, 2.02 mmol). The mixture was heated at 100° C. for6 hours. After cooling to room temperature the reaction mixture wasdiluted with ethyl acetate, washed with water (×3), brine (×1), driedover magnesium sulphate and concentrated in vacuo. The residue waspurified on silica gel eluting with a mixture of 0.88 ammoniasolution:methanol:dichloromethane (0.5:4.5:95) to furnish the titlecompound (0.98 g, 20%); MS (ES+) m/e 332 [M+H]⁺.

Step 2:4-(1-{(2S,5R)-2,5-Dimethyl-4-[4-(3-piperidin-1-yl-propoxy)-phenyl]-piperazin-1-yl}-methanoyl)-benzonitrile

The title compound was prepared from the product of step 1 (0.13 g, 0.38mmol) and 4-cyanobenzoic acid (0.11 g, 0.76 mol) using the proceduredetailed in Example 375, (0.097 g, 57%); MS (ES+) m/e 461 [M+H]⁺.

EXAMPLES 455-458

E455 to E458 were prepared from Example 454 step 1 with the appropriatecarboxylic acids indicated in the table below using the proceduredetailed in Example 375.

MS (ES+) m/e Compound Carboxylic Acid [M + H]⁺.1-{(2R,5R)-2,5-Dimethyl-4-[4-(3-piperidin-1-yl- Benzoic acid 436propoxy)-phenyl]-piperazin-1-yl}-1-phenyl- methanone (E455)1-{(2R,5R)-2,5-Dimethyl-4-[4-(3-piperidin-1-yl- Isonicotinic acid 437propoxy)-phenyl]-piperazin-1-yl}-1-pyridin-4- yl-methanone (E456)1-{(2R,5R)-2,5-Dimethyl-4-[4-(3-piperidin-1-yl- 4-(1-Pyrrolidin-1-yl-534 propoxy)-phenyl]-piperazin-1-yl}-1-[4-(1- methanoyl)-benzoicpyrrolidin-1-yl-methanoyl)-phenyl]-methanone acid (J. Med. Chem., (E457)2003, 46(10), 1845-1857) 1-{(2R,5R)-2,5-Dimethyl-4-[4-(3-piperidin-1-yl-tetrahydro-pyran-4- 444 propoxy)-phenyl]-piperazin-1-yl}-1- carboxylicacid (tetrahydro-pyran-4-yl)-methanone (E458)

EXAMPLE 4591-{(2R,5R)-2,5-Dimethyl-4-[4-(3-piperidin-1-yl-propoxy)-phenyl]-piperazin-1-yl}-1-morpholin-4-yl-methanone(E459)

A mixture of the product from Example 454 step 1 (0.20 g, 0.60 mol),4-morpholine carbonyl chloride (0.082 g, 0.55 mol), triethylamine (0.067g, 0.66 mol) in dichloromethane (8 ml) was stirred at room temperaturefor 18 hours. The mixture was filtered through am SCX column elutingwith methanol followed by 0.880 ammonia solution:methanol (1:9) toafford the title compound (0.18 g, 66%); MS (ES+) m/e 445 [M+H]⁺.

EXAMPLE 4604-(1-{5-[4-(3-Piperidin-1-yl-propoxy)-phenyl]-2,5-diaza-bicyclo[2.2.1]hept-2-yl}-methanoyl)benzonitrile (E460)

Step 1: 5-[4-(3-Piperidin-1-yl-propoxy)-phenyl]-2,5-diaza-bicyclo[2.2.1]heptane-carboxylic acid tert butyl ester

The title compound was prepared from example 316, step 1(1-[3-(4-Iodo-phenoxy)-propyl]-piperidine) (0.25 g, 0.72 mmol) and2,5-Diaza-bicyclo[2.2.1] heptane carboxylic acid tert butyl ester (0.17g 0.87 mmol) using the procedure described for example 454, step 1(0.313g, 84%); MS (ES+) m/e 416 [M+H]⁺.

Step 2: 2-[4-(3-Piperidin-1-yl-propoxy)-phenyl]-2,5-diaza-bicyclo[2.2.1]heptane

The title compound was prepared from the product of step 1 (0.31 g, 0.75mmol) using the procedure detailed in description D11; MS (ES+) m/e 316[M+H]⁺.

Step 3:4-(1-{5-[4-(3-Piperidin-1-yl-propoxy)-phenyl]-2,5-diaza-bicyclo[2.2.1]hept-2-yl}-methanoyl)benzonitrile

The title compound was prepared from the product of step 2 (0.23 g, 0.73mmol) and 4-cyanobenzoic acid (0.21 g, 1.45 mmol) using the proceduredetailed in Example 375, (0.27 g, 83%); MS (ES+) m/e 445 [M+H]⁺.

EXAMPLE 4614-(1-{4-[2-Chloro-4-(3-piperidin-1-yl-propoxy)-phenyl]-piperazin-1-yl}-methanoyl)-benzonitrile(E461)

Step 1: 1-[3-(4-Bromo-3-chloro-phenoxy)-propyl]-piperidine

The title compound was prepared from 1-(3-Chloropropyl)piperidinehydrochloride (2.38 g, 12 mmol) and 4-bromo-3-chloro-phenol (2.07 g, 10mmol) using the procedure detailed in Example 305, step 2, (3.42 g); MS(ES+) m/e 333 [M+H]⁺.

Step 2:4-[2-Chloro-4-(3-piperidin-1-yl-propoxy)-phenyl]-piperazine-1-carboxylicacid tert-butyl ester

The title compound was prepared from the product of step 1 (0.6 g, 1.8mmol) and 1,1-dimethylethyl 1-piperazinecarboxylate (0.40 g, 2.14 mmol)using the procedure detailed in Example 305, step 3 (0.46 g); MS (ES+)m/e 439 [M+H]⁺.

Step 3: 1-[2-Chloro-4-(3-piperidin-1-yl-propoxy)-phenyl]-piperazine

The title compound was prepared from the product of step 2 using theprocedure of Example 295 Step 5 (0.240 g); MS (ES+) m/e 338 [M+H]⁺

Step 4:4-(1-{4-[2-Chloro-4-(3-piperidin-1-yl-propoxy)-phenyl]-piperazin-1-yl}-methanoyl)-benzonitrile

The title compound was prepared from the product of step 3 (0.120 g,0.36 mmol) and 4-Cyanobenzoic acid (105 mg, 0.712 mmol) using theprocedure of Example 305 Step 5 (0.130 g); MS (ES+) m/e 468 [M+H]

EXAMPLE 4621-Phenyl-1-{4-[4-(3-pyrrolidin-1-yl-propoxy)-phenyl]-piperazin-1-yl}-methanone(E462)

Step 1:1-{4-[4-(3-Chloro-propoxy)-phenyl]-piperazin-1-yl}-1-phenyl-methanone

The title compound was prepared from the product of Example 295, Step 3(4-[4-(phenylcarbonyl)-1-piperazinyl]phenol) (1 g, 3.55 mmol) and1-bromo-3-chloro propane (0.67 g, 4.25 mmol) using the procedure ofDescription 9 (1.3 g); MS (ES+) m/e 359 [M+H].

Step 2:1-Phenyl-1-{4-[4-(3-pyrrolidin-1-yl-propoxy)-phenyl]-piperazin-1-yl}-methanone

The title compound was prepared from the product of step 1 (0.2 g, 0.56mmol) and pyrrolidine (0.047 g, 0.67 mmol) using the procedure ofDescription 10 (0.15 g); MS (ES+) m/e 394 [M+H].

EXAMPLES 463-464

E463 to E464 were prepared from Example 462 step 1 with the appropriateamine indicated in the table below using the procedure detailed inDescription 10.

MS (ES+) m/e Example Carboxylic Acid [M + H]⁺. 1-(4-{4-[3-(3,3-Difluoro-3,3-difluoro-pyrrolidine 430 pyrrolidin-1-yl)-propoxy]- (Synlett, 1995,1, 55-57) phenyl}-piperazin- 1-yl)-1-phenyl-methanone (E463)1-(4-{4-[3-(4,4-Difluoro-piperidin- 4,4-Difluoro-piperidine 4441-yl)-propoxy]-phenyl}-piperazin- (Tetrahedron, 1977,1-yl)-1-phenyl-methanone (E464) 33(14), 1707-1710)

EXAMPLE 4651-(1-Naphthalenylcarbonyl)-4-[2-(4-{[3-(1-piperidinyl)propyl]oxy}phenyl)ethyl]piperazine,formate (E465)

E465a:1-(1-Naphthalenylcarbonyl)-4-(2-{4-[(phenylmethyl)oxy]phenyl}ethyl)piperazine

A mixture of 1-(2-bromoethyl)-4-[(phenylmethyl)oxy]benzene (533 mg) and1-(1-naphthalenylcarbonyl)piperazine (440 mg) was partially dissolved in1-methyl-2-pyrrolidinone (2 ml) and treated with diisopropylethylamine(0.956 ml). The resulting reaction mixture was heated in a microwaveoven at 160° C. for a fixed hold time of 12 min. The mixture waspartitioned between ethyl acetate and water and the organic phase waswashed with water and saturated brine, dried (MgSO₄) and evaporated. Theresidue was loaded on to an SCX-2 SPE cartridge, which was eluted withmethanol followed by 2M methanolic ammonia. The methanolic ammoniafraction was evaporated, and the residue was further purified bychromatography on a silica SPE bond elut cartridge eluting with 3%methanol-1% triethylamine-dichloromethane to give the title compound(583 mg). LCMS RT=2.79 min.

E465b: 4-{2-[4-(1-Naphthalenylcarbonyl)-1-piperazinyl]ethyl}phenol

1-(1-Naphthalenylcarbonyl)-4-(2-{4-[(phenylmethyl)oxy]phenyl}ethyl)piperazine(E465a) (2.33 g) and 20% palladium hydroxide on carbon (800 mg) inethanol (50 ml) were stirred at room temperature under an atmosphericpressure of hydrogen. After 24 h more palladium catalyst (800 mg) wasadded and stirring continued for an additional 72 h. The reactionmixture was filtered through celite, washed with ethanol and thefiltrate and washings combined and evaporated under vacuum to give thetitle compound (1.84 g). LCMS RT=2.20 min.

E465c:1-(2-{4-[(3-Chloropropyl)oxy]phenyl}ethyl)-4-(1-naphthalenylcarbonyl)piperazine

4-{2-[4-(1-Naphthalenylcarbonyl)-1-piperazinyl]ethyl}phenol (E465b) (500mg), 1-bromo-3-chloropropane (0.165 ml) and potassium carbonate (481 mg)in 2-butanone (25 ml) were heated to reflux for 18 h. More1-bromo-3-chloropropane (0.165 ml) was added and heating continued for 6h. The reaction mixture was partitioned between ethyl acetate and water.The aqueous phase was re-extracted with ethyl acetate and the combinedorganic extracts were washed with saturated brine, dried (MgSO₄) andevaporated. The crude material was purified by chromatography on asilica SPE bond elut cartridge eluting with cyclohexane followed by agradient of 0-5% methanol-dichloromethane-1% triethylamine to give thetitle compound (582 mg). LCMS RT=2.67.

E465d:1-(1-Naphthalenylcarbonyl)-4-[2-(4-{[3-(1-piperidinyl)propyl]oxy}phenyl)ethyl]piperazine,formate

1-(2-{4-[(3-Chloropropyl)oxy]phenyl}ethyl)-4-(1-naphthalenylcarbonyl)piperazine(E465c) (50 mg), potassium carbonate (95 mg), potassium iodide (95 mg)and piperidine (0.067 ml) in 2-butanone (2 ml) were heated to reflux for24 h. The reaction mixture was partitioned between dichloromethane andwater. The aqueous layer was re-extracted and the combined organicextracts were concentrated and purified by mass directed preparativeHPLC to give the title compound (42 mg). LCMS RT=2.02 min. ES+ve m/z 486(M+H)⁺.

EXAMPLES 466-474 EXAMPLES 466-474 WERE PREPARED IN AN ARRAY FORMAT USINGTHE SAME METHOD described in Example 465d from1-(2-{4-[(3-chloropropyl)oxy]phenyl}ethyl)-4-(1-naphthalenylcarbonyl)piperazine(0.114 mmol), the appropriate secondary amine (6 eq), potassiumcarbonate (6 eq) and potassium iodide (5 eq) in 2-butanone (2 ml). Theproducts were purified by mass directed auto-preparative HPLC to providethe compounds as formate salts.

RT Mass Ion Example Structure (min) (M + H)⁺ 466

2.09 500 467

2.07 500 468

2.13 514 469

2.08 500 470

2.00 472 471

2.06 500 472

2.18 514 473

2.19 514 474

2.28 528

EXAMPLE 4751-(1-Naphthalenylcarbonyl)-4-[2-(4-{[2-(1-piperidinyl)ethyl]oxy}phenyl)ethyl]piperazine(E475)

E475a:1-(2-{4-[(2-Chloroethyl)oxy]phenyl}ethyl)-4-(1-naphthalenylcarbonyl)piperazine

Was prepared from4-{2-[4-(1-naphthalenylcarbonyl)-1-piperazinyl]ethyl}phenol and1-bromo-2-chloroethane using the same method as described in Example465c. LCMS RT 2.52 min.

E475b:1-(1-Naphthalenylcarbonyl)-4-[2-(4-{[2-(1-piperidinyl)ethyl]oxy}phenyl)ethyl]piperazine

1-(2-{4-[(2-Chloroethyl)oxy]phenyl}ethyl)-4-(1-naphthalenylcarbonyl)piperazine(E475a) (23 mg) potassium carbonate (45 mg), potassium iodide (45 mg)and piperidine (0.032 ml) in 2-butanone (2 ml) were heated to reflux for48 h. The reaction mixture was partitioned between dichloromethane andwater. The aqueous layer was re-extracted and the combined organicextracts were concentrated and purified by mass directed preparativeHPLC to give the title compound (9.9 mg). LCMS RT=1.97 min. ES+ve m/z472 (M+H)⁺.

EXAMPLES 476-479

Examples 476-479 were prepared in an array format using the same methoddescribed in Example 465d from1-(2-{4-[(2-chloroethyl)oxy]phenyl}ethyl)-4-(1-naphthalenylcarbonyl)piperazine(0.0544 mmol), the appropriate secondary amine (6 eq), potassiumcarbonate (6 eq) and potassium iodide (5 eq) in 2-butanone (2 ml). Theproducts were purified by mass directed auto-preparative HPLC to providethe compounds as formate salts.

RT Mass Ion Example Structure (min) (M + H)⁺ 476

2.08 486 477

2.13 500 478

2.10 486 479

1.98 486

EXAMPLES 480-499

Examples 480-499 were prepared in an analogous manner to the proceduredescribed for Example 62

RT Mass Ion Example Structure (min) (M + H)⁺ 480

2.36 505 481

2.24 464 482

2.54 547 483

2.61 561 484

2.59 574 485

2.32 524 486

2.42 520 487

2.43 588 488

2.20 538 489

2.32 534 490

2.24 510 491

2.36 519 492

2.33 532 493

2.07 482 494

2.24 478 495

2.20 496 496

2.50 546 497

2.38 492 498

2.42 492 499

2.40 546

EXAMPLE 5001-Phenyl-4-{2-[4-(3-piperidin-1-ylpropoxy)phenyl]ethyl}piperazinetrifluoroacetate (E500)

The title compound was prepared from D42 using the procedure describedin Example 229d.

RT=1.86 min, ES+ve m/z 408

EXAMPLE 5011-(5-tert-Butyl-2-methoxybenzoyl)-4-[4-(3-piperidin-1-ylpropoxy)phenyl]piperazine(E501)

The title compound was prepared from D11 using the procedure describedin Example 76c. RT=2.61 min, ES+ve m/z 494

EXAMPLE 5021-(3-{4-[4-(5-Isopropyl-2-methylbenzoyl)piperazin-1-yl]phenoxy}propyl)azepane(E502)

E502a: 1-[3-(4-piperazin-1-ylphenoxy)propyl]azepane

The title compound was prepared using an analogous method to thatdescribed in Example 76b.

RT=1.42 min, ES+ve m/z 318

E502b:1-(3-{4-[4-(5-Isopropyl-2-methylbenzoyl)piperazin-1-yl]phenoxy}propyl)azepane

The title compound was prepared from E502a using the procedure describedin Example 76c. RT=2.65 min, ES+ve m/z 478

EXAMPLE 5031-(3-{4-[4-(5-Ethyl-2-methylbenzoyl)piperazin-1-yl]phenoxy}propyl)azepane(E503)

The title compound was prepared from E502a using the procedure describedin Example 76c.

RT=2.57 min, ES+ve m/z 464

All publications, including but not limited to patents and patentapplications, cited in this specification are herein incorporated byreference as if each individual publication were specifically andindividually indicated to be incorporated by reference herein as thoughfully set forth.

Biological Data

A membrane preparation containing histamine H3 receptors may be preparedin accordance with the following procedures:

(i) Generation of Histamine H3 Cell Line

DNA encoding the human histamine H3 gene (Huvar, A. et al. (1999) Mol.Pharmacol. 55(6), 1101-1107) was cloned into a holding vector, pcDNA3.1TOPO (InVitrogen) and its cDNA was isolated from this vector byrestriction digestion of plasmid DNA with the enzymes BamH1 and Not-1and ligated into the inducible expression vector pGene (InVitrogen)digested with the same enzymes. The GeneSwitch™ system (a system wherein transgene expression is switched off in the absence of an inducer andswitched on in the presence of an inducer) was performed as described inU.S. Pat. Nos. 5,364,791; 5,874,534; and 5,935,934. Ligated DNA wastransformed into competent DH5α E. coli host bacterial cells and platedonto Luria Broth (LB) agar containing Zeocin™ (an antibiotic whichallows the selection of cells expressing the sh ble gene which ispresent on pGene and pSwitch) at 50 μg ml⁻¹. Colonies containing there-ligated plasmid were identified by restriction analysis. DNA fortransfection into mammalian cells was prepared from 250 ml cultures ofthe host bacterium containing the pGeneH3 plasmid and isolated using aDNA preparation kit (Qiagen Midi-Prep) as per manufacturers guidelines(Qiagen).

CHO K1 cells previously transfected with the pSwitch regulatory plasmid(InVitrogen) were seeded at 2×10e6 cells per T75 flask in CompleteMedium, containing Hams F12 (GIBCOBRL, Life Technologies) mediumsupplemented with 10% v/v dialysed foetal bovine serum, L-glutamine, andhygromycin (100 μg ml⁻¹), 24 hours prior to use. Plasmid DNA wastransfected into the cells using Lipofectamine plus according to themanufacturer's guidelines (InVitrogen). 48 hours post transfection cellswere placed into complete medium supplemented with 500 μg ml⁻¹ Zeocin™.

10-14 days post selection 10 nM Mifepristone (InVitrogen), was added tothe culture medium to induce the expression of the receptor. 18 hourspost induction cells were detached from the flask using ethylenediaminetetra-acetic acid (EDTA; 1:5000; InVitrogen), following several washeswith phosphate buffered saline pH 7.4 and resuspended in Sorting Mediumcontaining Minimum Essential Medium (MEM), without phenol red, andsupplemented with Earles salts and 3% Foetal Clone II (Hyclone).Approximately 1×10e7 cells were examined for receptor expression bystaining with a rabbit polyclonal antibody, 4a, raised against theN-terminal domain of the histamine H3 receptor, incubated on ice for 60minutes, followed by two washes in sorting medium. Receptor boundantibody was detected by incubation of the cells for 60 minutes on icewith a goat anti rabbit antibody, conjugated with Alexa 488 fluorescencemarker (Molecular Probes). Following two further washes with SortingMedium, cells were filtered through a 50 μm Filcon™ (BD Biosciences) andthen analysed on a FACS Vantage SE Flow Cytometer fitted with anAutomatic Cell Deposition Unit. Control cells were non-induced cellstreated in a similar manner. Positively stained cells were sorted assingle cells into 96-well plates, containing Complete Medium containing500 μg ml⁻¹ Zeocin™ and allowed to expand before reanalysis for receptorexpression via antibody and ligand binding studies. One clone, 3H3, wasselected for membrane preparation.

(ii) Membrane Preparation from Cultured Cells

All steps of the protocol are carried out at 4° C. and with pre-cooledreagents. The cell pellet is resuspended in 10 volumes of buffer A2containing 50 mM N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid(HEPES) (pH 7.40) supplemented with 10e-4M leupeptin(acetyl-leucyl-leucyl-arginal; Sigma L2884), 25 μg/ml bacitracin (SigmaB0125), 1 mM ethylenediamine tetra-acetic acid (EDTA), 1 mMphenylmethylsulfonyl fluoride (PMSF) and 2×10e-6M pepstain A (Sigma).The cells are then homogenised by 2×15 second bursts in a 1 litre glassWaring blender, followed by centrifugation at 500 g for 20 minutes. Thesupernatant is then spun at 48,000 g for 30 minutes. The pellet isresuspended in 4 volumes of buffer A2 by vortexing for 5 seconds,followed by homogenisation in a Dounce homogeniser (10-15 strokes). Atthis point the preparation is aliquoted into polypropylene tubes andstored at −70° C.

(iii) Generation of Histamine H1 Cell Line

The human H1 receptor was cloned using known procedures described in theliterature [Biochem. Biophys. Res. Commun. 1994, 201(2), 894]. Chinesehamster ovary cells stably expressing the human H1 receptor weregenerated according to known procedures described in the literature [Br.J. Pharmacol. 1996, 117(6), 1071].

Compounds of the invention may be tested for in vitro biologicalactivity in accordance with the following assays:

(I) Histamine H3 Binding Assay

For each compound being assayed, in a white walled clear bottom 96 wellplate, is added:—

(a) 100 μl of test compound (or 100 of iodophenpropit (a known histamineH3 antagonist) at a final concentration of 10 mM) diluted to therequired concentration in 10% DMSO;(b) 100 μl ¹²⁵I 4-[3-(4-iodophenylmethoxy)propyl]-1H-imidazolium(iodoproxyfan) (Amersham; 1.85 MBq/μl or 50 μCi/ml; Specific Activity˜2000 Ci/mmol) diluted to 200 pM in assay buffer (50 mMTris(hydroxymethyl)aminomethane buffer (TRIS) pH 7.4, 0.5 mMethylenediamine tetra-acetic acid (EDTA)) to give 20 pM finalconcentration; and(c) 800 bead/membrane mix prepared by suspending Scintillation ProximityAssay (SPA) bead type WGA-PVT at 100 mg/ml in assay buffer followed bymixing with membrane (prepared in accordance with the methodologydescribed above) and diluting in assay buffer to give a final volume of800 which contains 7.5 μg protein and 0.25 mg bead per well-mixture waspre-mixed at room temperature for 60 minutes on a roller.

The plate is shaken for 5 minutes and then allowed to stand at roomtemperature for 3-4 hours prior to reading in a Wallac Microbeta counteron a 1 minute normalised tritium count protocol. Data was analysed usinga 4-parameter logistic equation.

(II) Histamine H3 Functional Antagonist Assay

For each compound being assayed, in a white walled clear bottom 96 wellplate, is added:—

(a) 100 of test compound (or 100 of guanosine 5′-triphosphate (GTP)(Sigma) as non-specific binding control) diluted to requiredconcentration in assay buffer (20 mMN-2-Hydroxyethylpiperazine-N′-2-ethanesulfonic acid (HEPES)+100 mMNaCl+10 mM MgCl₂, pH7.4 NaOH);(b) 600 bead/membrane/GDP mix prepared by suspending wheat germagglutinin-polyvinyltoluene (WGA-PVT) scintillation proximity assay(SPA) beads at 100 mg/ml in assay buffer followed by mixing withmembrane (prepared in accordance with the methodology described above)and diluting in assay buffer to give a final volume of 600 whichcontains 10′4 protein and 0.5 mg bead per well-mixture is pre-mixed at4° C. for 30 minutes on a roller and just prior to addition to theplate, 10 μM final concentration of guanosine 5′ diphosphate (GDP)(Sigma; diluted in assay buffer) is added;

The plate is incubated at room temperature to equilibrate antagonistwith receptor/beads by shaking for 30 minutes followed by addition of:

(c) 100 histamine (Tocris) at a final concentration of 0.3 μM; and(d) 200 guanosine 5′ [γ35-S] thiotriphosphate, triethylamine salt(Amersham; radioactivity concentration=37 kBq/μl or 1 mCi/ml; SpecificActivity 1160 Ci/mmol) diluted to 1.9 nM in assay buffer to give 0.38 nMfinal. The plate is then incubated on a shaker at room temperature for30 minutes followed by centrifugation for 5 minutes at 1500 rpm. Theplate is read between 3 and 6 hours after completion of centrifuge runin a Wallac Microbeta counter on a 1 minute normalised tritium countprotocol. Data is analysed using a 4-parameter logistic equation. Basalactivity used as minimum i.e. histamine not added to well.

(III) Histamine H1 Functional Antagonist Assay

Compounds are assayed in a black walled clear bottom 384-well plate withcells seeded at 10000 cells/well. Tyrodes buffer is used throughout(NaCl 145 mM, KCl 2.5 mM, HEPES 10 mM, glucose 10 mM, MgCl₂ 1.2 mM,CaCl₂1.5 mM, probenecid 2.5 mM, pH adjusted to 7.40 with NaOH 1.0 M).Each well is treated with 10 μl of a solution of FLUO4AM (10 μM inTyrodes buffer at pH 7.40) and plates are then incubated for 60 minutesat 37° C. Wells are then washed with Tyrodes buffer using a EMBLA cellwasher system, leaving 400 buffer in each well, and then treated with 10μl of test compound in Tyrodes buffer. Each plate is incubated for 30min to allow equilibration of the test compound with the receptor. Eachwell is then treated with 10 μl of histamine solution in Tyrodes buffer.

Functional antagonism is indicated by a suppression of histamine inducedincrease in fluorescence, as measured by the FLIPR system (MolecularDevices). By means of concentration effect curves, functional potenciesare determined using standard pharmacological mathematical analysis.

Results

The compounds of Examples E1-260, 263-479 and E499-503 were tested inthe histamine H3 functional antagonist assay and exhibitedantagonism>6.5 pK_(b). More particularly, the compounds of Examples E1,E3, E10, E12-14, E16-20, E21, E23, E24, E31, E33, E35-37, E40-42,E46-48, E51, E255-256, E258-260, E263, E265-267, E268-271, E273-274,E277-280, E284-288, E290-293, E295, E309, E311, E314-315, E317,E319-329, E331, E333, E342, E344, E346-348, E350, E352, E354-355,E361-363, E368, E374, E378, E380, E384, E386, E389, E391-393, E396-E399,E405, E407, E410-411, E414-415, E420-421, E423-424, E429-431, E434-435,E436-445, E449, E452-453 and E455-459 exhibited antagonism>8.4 pK_(b).Yet more particularly, the compounds of Examples E255, E259, E263, E269,E271, E274, E285-287, E292-293, E333, E344, E346 and E374 exhibitedantagonism>9.0 pK_(b).

The compounds of Examples E53-254, E465-479 and E499-503 were tested inthe histamine H1 functional antagonist assay and exhibitedantagonism>6.5 pK_(b). More particularly, the compounds of Examples E60,E64-65, E67, E70, E84, E87, E91, E93, E95, E98, E100, E108-110, E112,E114-115, E135-136, E162, E171, E188-189, E195, E199, E206-212,E214-219, E224, E229, E231, E235, E242, E244, E466, E468-474 andE500-503 exhibited antagonism>7.3 pK_(b).

1. A compound of formula (I)

wherein: R¹ represents heteroaryl, optionally substituted by one ormore: halogen; trifluoromethyl; —C₁₋₆alkyl optionally substituted byCOOR¹⁵; —C₁₋₆alkoxy optionally substituted by COOR¹⁵; C₁₋₆ alkenyl;NR¹⁵R¹⁶; or C₁₋₆alkylthio groups, and in which R¹⁵ and R¹⁶ independentlyrepresent hydrogen, C₁₋₆alkyl or C₃₋₈cycloalkyl or together may be fusedto form a 5- to 7-membered non-aromatic heterocyclic ring optionallyinterrupted by an O or S atom and optionally substituted by halogen,C₁₋₆alkyl or —C₁₋₆alkylC₁₋₆alkoxy group; wherein R¹⁵ and R¹⁶independently represent hydrogen, C₁₋₆alkyl or C₃₋₈cycloalkyl ortogether may be fused to form a 5- to 7-membered non-aromaticheterocyclic ring optionally interrupted by an O or S atom andoptionally substituted by a halogen, C₁₋₆alkyl or C₁₋₆alkylC₁₋₆alkoxygroup; Z is a bond or CO; m is 0 or 2; p is 1; R³ represents—(CH₂)_(q)—NR¹¹R¹² in which q represents 3 and NR¹¹R¹² representspyrrolidinyl, piperidinyl, azepanyl or azocanyl optionally substitutedby one or more C₁₋₆ alkyl groups; or a pharmaceutically acceptable saltthereof.
 2. A compound according to claim 1, in which R¹ representsoptionally substituted benzofuranyl, indolyl, or quinolinyl.
 3. Acompound according to claim 1, wherein m is
 0. 4. A compound accordingto claim 1, wherein R¹ is optionally substituted by 1, 2 or 3substituents selected from chlorine, fluorine, bromine, trifluoromethyl,methyl, ethyl, isopropyl, propyl or t-butyl (wherein the methyl, ethyl,isopropyl, propyl or t-butyl is optionally substituted by COOR¹⁵),methoxy (optionally substituted by COOR¹⁵), ethenyl, N(Me)₂ or —S-ethyl.5. A compound according to claim 1, wherein NR¹¹R¹² representspyrrolidinyl, piperidinyl, azepanyl or azocanyl optionally substitutedby one or more methyl or ethyl groups.
 6. A compound according to claim1 in which NR¹¹R¹² represents unsubstituted pyrrolidinyl, piperidinyl,azepanyl or azocanyl.
 7. A pharmaceutical composition which comprises acompound of formula (I) as defined in claim 1 or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier orexcipient.
 8. A method of treatment of diseases of the upper respiratorytract which comprises administering to a host in need thereof aneffective amount of a compound of formula (I) as defined in claim 1 or apharmaceutically acceptable salt thereof.
 9. A method of treatmentaccording to claim 8 in which the disease is allergic rhinitis.